Obesity Small Molecules

ABSTRACT

The present invention relates to new therapies to treat obesity and related diseases, as well as for reducing triglyceride levels and body weight.

The present invention relates to the field of pharmaceutical compounds and methods for the treatment of overweight and obesity.

The world health organization currently estimates that as of 2009 over 1 billion individuals worldwide are overweight. Almost one third of these individuals are clinically obese, markedly raising their chances of cardiovascular disease, type-2 diabetes, cancer, and stroke. The regulation of body fat content in animals results from the integration of multiple nutrient, sensory, and hormonal inputs primarily at the level of the brain and adipose tissues. This integrative network is influenced not only by genetics, but also by circadian rhythm and physical and social environments. Obesity is thus, a complex, systems level disease.

Spurned by the discovery of leptin, tremendous progress has been made in identifying the molecular players and pathways regulating adiposity. The impressive bounds made through the study of gene-targeted mice and the tracking of monogenic obesity disorders in humans, have been complemented by studies in lower organisms. Virtually all key metabolic regulators examined to date display conserved functions across phyla, including for instance, insulin signaling, mTOR, and key lipases such as ATGL. Similar to mammals, model organisms such as Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans employ multiple molecular and tissue-based regulatory networks to balance energy needs, nutritional state, and aging and thus represent potent genomics tools for the study of metabolism. For instance, an RNAi feeding model was used to identify potential regulators of fat storage in the C. elegans genome.

It is a goal of the present invention to identify further genes, enzymatic pathways and active compounds for their modulation suitable for the treatment of triglyceride dysfunction, overweight and obesity.

The present invention therefore provides a method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1. E.g. a therapeutic dose disclosed or approved for other therapeutic uses for each of these compounds can be used.

In a further aspect the present invention provides a method of reducing triglyceride levels, in particular LDL levels, in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.

In a related aspect the present invention provides the use of a compound of table 1 for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat obesity in a subject. Also provided are these compounds for use in the therapies disclosed herein. The invention is further defined by the subject matter of the claims.

In particular the present invention relates to use of the following compounds for the above tratments, in particular for reducing weight and/or body fat in a subject:

-   -   Vandetanib,     -   Dasatinib,     -   Tanespimycin (17-allylamino-demethoxygeldamycin, “17-AAG”),     -   S-17092,     -   Sorafenib,     -   Lintopride,     -   Fenoprofen,     -   Sulfaphenazole,     -   Fluticasone (including Fluticasone propionate, “Ubizol”),     -   Rolipram,     -   Febuxostat,     -   Verapamil (including Norverapamil),     -   a therapeutic compound selected from a modulator of gene CG9438,         or an ortholog thereof, in particular the human orthologue         CYP3A4, the compounds being selected from erlotinib, gefitinib         and lapatinib,     -   a therapeutic compound selected from a modulator of gene CG8222,         or an ortholog thereof, in particular the human orthologue KDR,         the compounds being selected from axitinib, pazopanib and         semaxanib (also known as Semaxinib or SU 5416),     -   a therapeutic compound selected from a modulator of gene CG6919,         or an ortholog thereof, in particular the human orthologue HTR4,         the compounds being selected from cisapride, mosapride,         piboserod, prucalopride, renzapride, tegaserod, tropisetron and         zacopride,         or any combination of the above compounds with any one or more         compounds selected from the compounds of table 1, preferably         with the compounds given above. However, in other embodiments         the compounds may be used alone in the inventive treatment         described herein. According to this embodiment the invention         provides for the inventive therapy wherein the compound is         administered as the only therapeutic compound active (or         indicated) in a treatment of reducing weight and/or body fat or         of obesity in a subject. In particular, the inventive compound,         especially Lintopride, is used for administration without a DPP         IV inhibitor as disclosed in the WP 2006/005613

The inventive use of the compounds given herein includes the use of any pharmaceutically acceptable salt or hydrate form thereof.

In preferred embodiments the inventive compounds are used in the treatment of obesity, in particular severe obesity. Obesity is defined as an excess of body fat. Body mass index (BMI—the ratio of body weight in kg to the square of the height of an individual in m), is a useful measure of fat distribution. Importantly it allows the stratification of patient categories to identify increased risk of morbidity and mortality and the identification of suitable interventions. Furthermore it provides a firm basis for the assessment of intervention strategies. The stratification of obesity using BMI is as follows. BMI ≦25=Overweight, BMI 25-29.99=Preobese, BMI 30-34.99=Obese class I, BMI 35-39.99=Obese class II, BMI 40=Obese class III (WHO 2000). Class II obesity is severe obesity and class III obesity is referred to as extreme obesity, associated with an extremely high risk of comorbidities including Type 2 diabetes mellitus; Hypertension; Dyslipidemia; Cardiovascular disease including Coronary artery disease, Stroke and Congestive heart failure; Nonalcoholic fatty liver disease (steatosis, steatohepatitis, cirrhosis); Respiratory disease including Obstructive sleep apnea, Obesity-hypoventilation syndrome, Asthma, Restrictive lung disease; Cancer; Osteoarthritis; Cholelithiasis; Gastroesophageal reflux disease; Gynecologic abnormalities including Infertility, Abnormal menses; Venous stasis; Skin problems such as Intertrigo and Cellulitis; Increased risk of complications during surgery or pregnancy; Urinary incontinence; Idiopathic intracranial hypertension (Hensrud et al., 2006). As the degree of obesity increases so does the risk of all cause mortality. Extreme obesity has been estimated to lead to a shortening of life of between 5 and 20 years depending on other factors including sex, age and racial group (Fontaine et al., 2003). Bariatric surgery is a common treatment for severely obese patients and the numbers of surgery performed per year is increasing along with the increased prevalence of obesity and in particular severe obesity. The number of bariatric surgeries performed in the US increased from 13,386 in 1998 to an estimated 170,000 in 2005 (Ecinosa et al., 2005). However only 0.6% of over 11 million extremely obese patients in 2002 are eligible for surgery actually underwent a bariatric procedure (Ecinosa et al., 2005). Furthermore extreme obesity is also associated with an increased prevalence of psychiatric illnesses. Between a half and two-thirds of all bariatric surgery candidates possess an Axis I psychiatric disorder such as depression, somatization, social phobia, hypochondriasis, or obsessive-compulsive disorder (Rosick et al., 2005; Sarwer et al., 2004).

The subject to be treated according to the present invention can be any non-human animal or a human. Preferably the subject is a mammal, in particular preferred embodiments a human.

According to the present invention obesity, diseases associated with obesity, e.g. diabetes, can be treated or prevented, in particular in the meaning of a prophylactic administration. “Preventing” or “prevention” herein does not require absolute success in the sense of an absolute prevention of a heart disease but indicates a reduced risk of developing a disease, or developing a disease with reduced severity. Likewise, “treatment” shall not be construed as an absolute cure, but may also relate to amelioration of the disease or disease symptoms.

“About” is used to refer to certain dosages that can vary from a given value, nevertheless with the same effects as the indicated dose. In some embodiments “about” may refer to +/−20% or 10% of a given value.

Preferably the compound is administered in a dosage sufficient to treat or prevent said diseases. Administration can e.g. be a single dose administration or a successive or repeated administration, e.g. twice a day, daily or in an interval of at least 1 day, at least 2 days, at least 3 days, at least 1 week, preferably at least 2 weeks, at least 4 weeks, at least 8 weeks or even more preferred at least 12 weeks.

According to a further preferred embodiment of the present invention, the compound is provided in a pharmaceutical composition or a medicament. The composition or medicament may comprise a pharmaceutical carrier. Pharmaceutical carrier substances serve for a better tolerance of the medicament and allow for a better solubility as well as a better bioavailability of the active substances contained in the medicament. Examples of this are emulsifiers, thickening agents, redox components, starch, alcohol solutions, polyethylene glycol or lipids. The choice of a suitable pharmaceutical carrier is highly dependent on the manner of administration. For oral administrations, liquid or solid carriers may be used, for injections, liquid final compositions are required. For cellular targeting suitable vehicles can be includes such as liposomes or microsomes.

Preferably, the medicament or the compound to be used according to the invention comprises buffer substances or tonic substances. By means of a buffer, the pH of the medicament can be adjusted to physiological conditions, and moreover, pH fluctuations can be attenuated, or buffered, respectively. An example thereof is a phosphate buffer. Tonic substances serve for adjusting the osmolarity and may comprise ionic substances, such as, e.g., inorganic salts, such as NaCl, or also non-ionic substances, such as, e.g. glycerol or carbohydrates.

The inventive compound or medicament can be administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or intraperitoneal, transdermal, transmucosal or inhalational. Preferred routes of administration of the inventive agent according to the present invention are parenteral routes, preferably intraperitoneal or intravenous administration, intravenous administration being specifically preferred. Intravenous administration can be performed e.g. via bolus injection or by continuous intravenous delivery over a longer time period (e.g. 30 min to 6 h, especially 1 to 3 h). Further routes include oral or transdermal or subcutaneous routes. In particular preferred is oral administration. For digestible agents, such as active proteins, peptides or siRNA, parenteral routes are preferred.

The medicament or the compound to be used according to the invention can be prepared to be suitable for oral or intranasal administration. These administration forms of the medicament of the present invention allow for a rapid an uncomplicated uptake of the active substances via the mucous membranes. For a nasal intake, nose drops or nose sprays are suitable. For an oral administration, solid or liquid medicaments may, e.g., be taken directly or in a dissolved or diluted state, respectively.

The medicament or compound to be used according to the invention can be prepared for an intravenous, intra-arterial, intramuscular, intravascular, systemic, intraperitoneal or subcutaneous administration. For this purpose, e.g., injections or transfusions are suitable. Administrations directly into the bloodstream have the advantage that the active substances of the medicament will be distributed in the entire body and will quickly reach the target tissue, in particular the heart muscle.

The compound may be administered in a effective therapeutic dose. Effective doses are in the range of dosages known for these compounds for other, non-obesity related administrations. In particular, for a specific use a dosage can be determined by a simple test using drosophila or mouse test systems, e.g. as shown in example 3. Preferably the dosage is determined in a mouse test, e.g. using DIO B6 mice, at six weeks of age, mice are fed high fat diet to induce obesity, e.g. a 60 kcal % fat diet. The appropriate dosage can be correlated with reduced obesity symptoms, in particular fat mass or body weight. Example dosages are at least 0.01 mg/kg, at least 0.1 mg/kg, at least 1 mg/kg, at least 10 mg/kg and/or up to 1 mg/kg, up to 10 mg/kg, up to 100 mg/kg, up to 1 g/kg, and any dosages in between. Preferred dosage ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100 mg/kg.

Vandetanib

Vandetanib also known as Zactima; ZD6474; 4-Bromo-2-fluorophenyl)-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinazolin-4-yl]-amine is an orally available tyrosine kinase inhibitor (TKI).

Vandetanib is currently in clinical trials for the treatment of various cancers, including colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma and medullary thyroid cancer. Vandetanib is currently under review by the FDA Oncologic Drugs Advisory Committee (ODAC) proposed to be indicated for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer.

It may be administered orally at doses ranging from 15 mg to 300 mg once daily. An oral dose of 300 mg once daily is the maximum tolerated dose in humans. Doses used in the clinic range between 100 mg and 300 mg.

Dasatinib

Dasatinib is also known as BMS-354825. Dasatinib is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib.

A recommended oral starting dose of dasatinib in chronic phase CML is 100 mg once daily. The recommended starting dose for accelerated, myeloid, or lymphoid blast phase CML or Philadelphia chromosome-positive ALL is 70 mg twice daily. Doses of up to 140 mg once daily have been used in patients with chronic phase CML, and up to 100 mg twice daily in those with advanced phase CML, or with ALL. It may also be administered 15 to 240 mg per day (60 kg adult human dose), preferably orally.

Sorafenib

Sorafenib and the tosylate salt form Sorafenib Tosylate (chemical name 4-(4-{3-[4-chloro-3(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide-4-methylbenzenesulfonate) inhibits tumour cell proliferation and angiogenesis by targeting RAF Kinases and VEGF Receptors. Sorafenib is generally prepared as its tosylate salt form. Sorafenib and pharmaceutically acceptable salts thereof are disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents also disclose processes for the preparation of sorafenib.

Sorafenib is approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma). The maximum tolerated does in humans is an oral administration of 400 mg twice daily. References: WO0042012, WO0041698 (incorporated herein by reference).

Sorafenib antagonizes activity of gene CG8222 (PDGF- and VEGF-receptor related). Whole body and fat body-specific knockdown of this gene resulted in a loss of trigylcerides in the fly. The human orthologue of this gene is KDR (kinase insert domain receptor (a type III receptor tyrosine kinase. It functions as mediator of endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3 and T-cell protein tyrosine phosphatase.

Sorafenib may be administered orally and has a half life of 25-48 hours. The dosage can be between 50 and 600 mg (adult human dose), preferably about 200 mg.

Tanespimycin

Tanespimycin, also known as 17-allylamino-demethoxygeldamycin (17-AAG) and KOS-953, is an ansamycin anti-biotic which acts as an anti-tumour agent. Specifically, Tanespimycin binds and inhibits Hsp90 (Heat shock protein 90). Hsp90 is a protein chaperone that binds to signalling proteins, known as client proteins. These client proteins include key cancer-relevant targets such as mutated p53, Bcr-Abl, Her2, Akt, Raf-1, B-Raf, and others. Tanespimycin is able to disrupt the Hsp90-client protein complexes and lead to the degradation of the client proteins. Tanespimycin and the related compound Alvespimycin (INN) also known as 17-dimethylamino-geldanamycin (17-DMAG) or KOS-1022 are less toxic analogues of geldanamycin (GA).

Tanespimycin has been investigated for the treatment of patients with Relapsed-refractory Multiple Myeloma, Metastatic Papillary or Clear Cell Renal Cell Carcinoma, Recurrent Advanced Ovarian Epithelial or Primary Peritoneal Cavity Cancer, Metastatic Breast Cancer and Refractory or Advanced Solid Tumours or Hematologic Malignancies.

Tanespimycin is water insoluble, and thus it is administered to patients intravenously using organic solvents such as DMSO. A formulation of tanespimycin, KOS-953, that contains Cremophory EL (polyethoxylated castor oil) rather than DMSO has also been developed. Recommended phase II doses of 295 mg/m2, 308 mg/m2, and 450 mg/m2 have been administered to patients.

Knock-down of the Drosophila gene CG1242 resulted in a reduction of triglyceride levels in the fly. The human orthologue of this gene is the heat shock protein HSP90AA1. HSP90 proteins are highly conserved molecular chaperones that have key roles in signal transduction, protein folding, protein degradation, and morphologic evolution. HSP90 proteins normally associate with other cochaperones and play important roles in folding newly synthesized proteins or stabilizing and refolding denatured proteins after stress. HSP90AA1 is one of the two major cytosolic HSP90 proteins.

In preferred embodiments 17-N-Allylamino-17-demethoxygeldanamycin may be administered i.p., i.v., or oral, preferably i.p., e.g. at doses of 60, 40, and 26.67 mg/kg i.p. and oral doses of 40 mg/kg. Preferably the dose may be between 1 mg/kg of body weight to 500 mg/kg, preferably at least 20 mg/kg or even above 80 mg/kg.

S-17092

“S-17092” or “S17092-1”, (2S,3aS,7aS)-1{[(R, R)-2-phenylcyclopropyl]carbonyl}-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole, is a selective inhibitor of the enzyme Prolyl endopeptidase. This enzyme is involved in the metabolic breakdown of a number of neuropeptide neurotransmitters in the brain and so inhibiting the action of the enzyme increases the activity of these neuropeptides. This produces nootropic effects which make S-17092 a promising and novel treatment for neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. S17092 might possess some mood-stabilizing potential in addition to its cognition-enhancing properties.

S-17092 has been administered orally to patients at doses of 100, 400, 800 and 1200 mg once daily (Morain et al., 2000).

Knockdown of the drosophila gene CG5355 resulted in a loss of triglyceride levels in the fly. Tissue specific deletion in the liver and fat body also lead to a reduction of triglyceride levels in the fly. A human orthologue of CG5355 is PREP. PREP (Prolyl endopeptidase) is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides.

Lintopride

Lintopride (also referred to as Lintopril) is a 5HT-4 antagonist with moderate SHT-3 antagonist properties. Lintopride has been shown in humans to increase the lower oesophageal sphincter (LOS) motility basal tone without affecting LOS physiological relaxation after swallowing and leads to an increase of peristaltic waves in the oesophagus.

It can be administered orally or intravenously and has been used at dosages of 0.1, 0.3, 0.5 mg/kg in humans.

Whole body and muscle specific knockdown of the Drosophila gene CG6919 lead to a reduction in triglyceride levels in the fly. The human orthologue of this gene is HTR4. This gene is a member of the family of serotonin receptors, which are G protein coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine). The gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various neurotransmitters.

Fenoprofen

Fenoprofen, non-steroidal anti-inflammatory drug, is a propionic acid derivative with analgesic, anti-inflammatory and antipyretic properties. Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain.

Whole body, neuronal and liver specific knockdown of CG8451 lead to a reduction of fly triglyceride levels. This gene is an orthologue of the human gene SLC5A8. Inflammatory drugs such fenoprofen function as blockers of this transporter.

Fenoprofen is taken orally at doses ranging from 200 mg up to a maximum recommended dose of 3.2 g per day.

Sulfaphenazole

Sulfaphenazole is a sulfonamide antibacterial and a specific inhibitor of CYP2C9. It blocks the pro-inflammatory and atherogenic effects of linoleic acid (increase in oxidative stress and activation of AP-1) mediated by CYP2C9.

Sulfaphenazole has been administered to patients by intravenous and intra-arterial perfusion (0.03 μg/100 ml tissue/min) (Giannarelli et al., 2009).

Whole body and liver specific knockdown of the fly gene CG3466 resulted in a reduction of triglyceride levels. CG3466 is a member of the cytochrome P450 enzyme family. Sulfaphenazole functions as an inhibitor of cytochrome function.

Fluticasone

Fluticasone propionate (Ubizol) is a synthetic corticosteroid derived from fluticasone used to treat asthma and allergic rhinitis (hay fever). It is also used to treat eosinophilic esophagitis. Fluticasone propionate is delivered as an aerosol formulation and is also available as a cream for the treatment of eczema and psoriasis.

A recent study has indicated that Fluticasone propionate functions as a Smoothened (Smo) agonist that activate Hedgehog signalling (Wang et al., 2010).

The maximum recommended dose for fluticasone propionate aqueous nasal spray is 200 micrograms daily. Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated.

Rolipram

Rolipram is a phosphodiesterase IV inhibitor with antidepressant properties. It is an anti-inflammatory drug being studied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects. Other beneficial effects of rolipram include improved long term memory, increased wakefulness, and increased neuroprotection. Rolipram shows promise in ameliorating Alzheimer's disease, Parkinson's disease and also in the regeneration of severed spinal cord axonal bodies.

Rolipram can be administered orally or intravenously usually at doses ranging from 0.001-10 mg per day.

Febuxostat

Febuxostat (INN) is an inhibitor of xanthine oxidase. Xanthine oxidase functions to successively oxidize both hypoxanthine and xanthine to uric acid. Inhibition of xanthine oxidase by febuxostat reduces production of uric acid. Febuxostat is indicated for use in the treatment of hyperuricemia and gout. The recommended dose is of 40 mg or 80 mg orally once daily.

Verapamil, Norverapamil

Verapamil and its salt Verapamil Hydrochloride is an L-type calcium channel blocker of the Phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class 4 antiarrhythmic. The maximum recommended human daily dose is 480 mg/day by oral administration.

Further preferred compounds are associated with the gene CG9438 and the human orthologue CYP3A4 from the list of erlotinib, gefitinib and lapatinib:

Erlotinib

Erlotinib, preferably used in its hydrochloride salt form (trade name Tarceva), is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).

Gefitinib

Gefitinib (trade name Iressa) is an EGFR inhibitor drug used in the treatment of advanced non-small cell lung cancer (NSCLC).

Lapatinib

Lapatinib, preferably used in the form of lapatinib ditosylate (USAN) (Tykerb/Tyverb, GSK), is an orally active drug for treatment of breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which disrupts the HER2 growth receptor pathway.

Further preferred compounds are associated with the gene CG8222 and its human orthologue KDR selected from the list of axitinib, pazopanib, and semaxanib (also known as Semaxinib or SU 5416):

Axitinib

Axitinib is a small molecule tyrosine kinase inhibitor. It has been shown to significantly inhibit growth of breast cancer in xenograft models and has been successful in trials with renal cell carcinoma (RCC) and several other tumour types.

Pazopanib

Pazopanib is a multi-targeted receptor tyrosine kinase inhibitor. It has been approved for treatment of renal cell carcinoma. Pazopanib may also be active in ovarian cancer and soft tissue sarcoma and in the treatment of non-small cell lung carcinoma.

Semaxanib (also known as Semaxinib or SU 5416)

Semaxanib is a tyrosine kinase inhibitor that has been withdrawn from clinical trials after failing to show efficacy in the treatment of patients with advanced stage colorectal cancer. Further preferred compounds are associated with the gene CG6919 and its human orthologue HTR4 selected from the list of cisapride, mosapride, piboserod, prucalopride, tegaserod, tropisetron, renzapride, and zacopride:

Cisapride

Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. Cisapride increases muscle tone in the esophageal sphincter in patients with gastroesophageal reflux disease. It has also been used to treat bowel constipation.

Mosapride

Mosapride is a gastroprokinetic agent which accelerates gastric emptying and is used for the treatment of acid reflux, irritable bowel syndrome and functional dyspepsia.

Piboserod

Piboserod (also known as SB 207266) is used for the treatment of atrial fibrillation and irritable bowel syndrome. It is also being investigated as a treatment for heart failure

Prucalopride

Prucalopride treats the impaired motility associated with chronic constipation, thus normalising bowel movements.

Renzapride

Renzapride is a gastroprokinetic agent and antiemetic, which was being investigated for the treatment of constipation predominant irritable bowel syndrome (IBS-C). It is also potentially effective for irritable bowel syndrome with alternating stool pattern (IBS-A). However it failed to show efficacy over placebo in Phase III clinical trials and development was discontinued.

Tegaserod

Tegaserod functions as a motility stimulant that stimulates gastrointestinal motility and the peristaltic reflex. It was approved for the treatment of irritable bowel syndrome and constipation.

Tropisetron

Tropisetron is an antiemetic used to treat nausea and vomiting following chemotherapy. It has also been used experimentally as an analgesic in the local treatment of tendinopathies and myofascial pain syndromes.

Zacopride

Zacopride been shown to have many activities including anxiolytic and nootropic effects. It has also been shown to have antiemetic and pro-respiratory effects, both reducing sleep apnea and reversing opioid-induced respiratory depression in animal studies.

The above examples show that the inventive obesity tests revealed pharmaceutical compounds that are well known to be therapeutically applicable for the treatment of human conditions and diseases. The compounds may now also be used for the treatment of obesity and associated secondary diseases such as diabetes or the metabolic syndrome. Of course the full list of compounds according to table 1 provides new therapeutic concepts.

Further compounds to be used in any form of treatment, e.g. in combination with the above compounds or for use alone, according to the present invention are selected from any one of (5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine, (E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)stilbazole)) 1-oxide, (melle-4)cyclosporin, 1-(1-cyclohexylethylamino)-4-phenylphthalazine, 1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine, 15-deoxyprostaglandin J2,17-(allylamino)-17-demethoxygeldanamycin, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin, 1-aminooxy-3-aminopropane, 1-beta-D-arabinofuranosyl-Cytosine, 1-carbamoyl-4-phenylpyrrolidone-2,1-Carboxyglutamic Acid, 1-deoxygalactonojirimycin, 1-hydroxymethylmidazolam, 2-[2-[2-[2-[2-amino-3-(4-hydroxyphenyl)-1-oxo-propyl]amino-1-oxo-ethyl]amino-1-oxo-ethyl]amino-1-oxo-3-phenyl-propyl]amino-4-methyl-pentanoic acid, 25-desacetylrifabutin, 2-AAF, 2-AAF, 2-AG, 2-AG, 2-AP, 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole, 2-DG, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone, 2-methoxyacetic acid [2-[2-[3-(1H-benzoimidazol-2-yl)propyl-methyl-amino]ethyl]-6-fluoro-1-isopropyl-tetralin-2-yl]ester, 2-methylarachidonyl-2′-fluoroethylamide, 2-phenyl-4-oxohydroquinoline, 2-propylquinoline, 3-(5-((4-(methylsulfonyl)-1-piperazinyl)methyl)-1H-indole-2-yl)quinolin-2(1H)-one, 3-AB, 3′-deamino-3′-hydroxydoxorubicin, 3-HF, 3-Methoxyoestradiol, 3-MF, 4-(4-(1-Amino-1-methylethyl)phenyl)-2-(4-(2-morpholin-4-yl-ethyl)phenylamino)pyrimidine-5-carbonitrile, 4′-epidoxorubicin, 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide, 4′-N-benzoylstaurosporine, 4PBA, 4-PCB, 5-(4′-(N-piperidinyl)phenylazo)indazole, 5-bromo-4-chloro-3-indolyl beta-galactoside, 5-carboxamidotryptamine, 5-demethylovalicin, 5′-O-(((2-decanoylamino-3-phenylpropyloxycarbonyl)amino)sulfonyl)uridine, 6′-N-methylsisomicin, 7 HC, 7,8-BF, 7C3MT, 7-hydroxystaurosporine, 7-ketocholesterol, 8-Hydroxy-2-(di-n-propylamino)tetralin, 8-hydroxyguanosine, 9-(2-hydroxy-3-nonyl)adenine, 9-beta-Derythrofuranosyladenine, 9-CRA, 9-hydroxy-risperidone, A-300-I, a-ADP, AAL 881, AATP, AB 2, abacavir, Abufene, Acenocoumarol, Acetidin, Acetorphan, acetoxymethyl-ester, Aclarubicin, ACNU, Acolen, ACON, actein, acteoside, Actihaemyl, Actosin, adalimumab, Adanon, ADMA, ADMA, Adofeed, Adrenor, Adrin, AEBSF, AEE 788, AG 1879, ajoene, Aklavin, alachlor, Alat, ALDA, Aldara, Aldocorten, alemtuzumab, Alendronate, Alfarol, Alfentanil, ALIMTA, aliskiren, Alli; Allnal, allylamino-demethoxy-geldanamycin, alpha-neoendorphin, alternagin-C, Alvesco, alvimopan, Am 80, Amatin, AMCHA, AMD 070, amentoflavone, Amiloride, Amine BB, Amiodarone, Amiodarone, amlexanox, Amlodipine, Ammo, Ampicillin, amprenavir, amrubicin, AMSA, amsonic acid, Anaboleen, Anandamide, Anco, and-carboxyfluorescein-diacetate-succinimidyl-ester, Androstenediol, anilinyl, Anisomycin, ANSA, antibiotic G 418, antibiotic H107, antineoplaston A10, Antizol, APAP, APDC, Aphidicolin, Aphidicolin, Aphloiol, apicidin, Apigenin, aplidine, aprepitant, APRL, Apsor, aptiganel, Aralen, arctiin, Arecoline, Areether, argatroban, aripiprazole, Armor, Artein, ASTA, astatine, Astemizole, atazanavir, Atorel, atorvastatin, Atosil, Atovaquone, ATRA, Auluton, aureobasidin A, Aurothioglucose, AuTM, Axert, axitinib, Axsain, azacyclonol, Azadc, azamulin, azanediyl group, azaspirane, azelastine, azelnidipine, azidoprazosin, Aziran, Azithromycin, Azor, Azur A, Azure B, BA (VAN), Baclofen, Bagren, baicalein, Barnidipine, BAY 11-7085, Beflavin, Benidipine, benzoyl-staurosporine, beraprost, Berbamine, berberine, bergamottin, bergaptol, BESTATIN, betacitronellol, beta-eudesmol, beta-funaltrexamine, beta-gamma-iminotriphosphate, bexarotene, Bezafibrate, BI D1870, biapigenin, BIBF 1000, BIBW 22, bifeprunox, Bisoprolol, Bisphenol A-Glycidyl Methacrylate, bizelesin, Bleomycin, BM 41.440, BMS 310705, BMS-262084, BMS453, BMS-470539, BMY 7378, Borrelia-burgdorferi, bortezomib, bosentan, bosutinib, Bo-Xan, Brefeldin A, bremazocine, bryostatin, Budesonide, bufalin, Bumetanide, Bupivacaine, Buprenorphine, Buspirone, Buthionine, Buthionine Sulfoximine, cabergoline, CACP, Calcijex, Calcimycin, calphostin C, Calyculin, Camptothecin, candesartan, candoxatril, candoxatrilat, Canef, CAPE, capsanthin, capsazepine, Carbamazepine, carbamic acid, Cardiolipins, Cardioplegic Solutions, carebastine, carfentanil, Carisoprodol, CARNOSOL, carvacrol, carvedilol, Casodex, caspofungin, casticin, catechins, CD 437, Cefotaxime, Ceftazidime, celecoxib, Celiprolol, CEP 701, cephalomannine, cerivastatin, Cerulenin, Cetirizine, Cetirizine, cetuximab, CGS 26303, CGS 35066, CGS 35601, Chloramphenicol, chloroprocaine, Chlorzoxazone, chymostatin, cicaprost, ciglitazone, Ciguatoxins, Cillora, cilostazol, Cimetidine, CINK4, Cipol N, Ciprofloxacin, Ciprol, Cisapride, Citalopram, Citox, CJ-15161, Cladribine, clavosine B, clavulone II, clobazam, Clodronic Acid, Clofazimine, Clofibric Acid, Clomipramine, Clonazepam, Clonidine, clonidinedisplacing substance, clopidogrel, clotiazepam, Clozapine, CMDBS 25, Co 2-1970, Colchicine, Cordanum, cornuside, costunolide, Cotinine, Cotrim, coumarin, coumarin, coumarin, coumermycins, CP 31398, CRA 026440, CREBtide, Crestor, Crodacid, cryptotanshinone, cryptoxanthin, Cyclandelate, cyclohexanecarboxylic acid (2-(4-(2-bromo-5-methoxybenzyl)piperazin-1-yl)ethyl)-(2-trifluoromethoxyphenyl)amide, cyclopamine, cyclopiazonic acid, cycloprodigiosin, cyclosporin G, cyclotheonamide A, Cyproterone Acetate, Cystamine, cytarabine, D 21266, DA 8159, DABS, Dacarbazine, DADA, DADSO, daidzein, Dalteparin, D-AM, danaproid, Danazol, Dapsone, Daral, Darifenacin, dasatinib, DAU 6285, Daunorubicin, dauricine, Dayfen, Dddd-PGD2, decursin, Deferoxamine, DEHP, dehydroaripiprazole, Dehydroepiandrosterone Sulfate, dehydroxymethylepoxyquinomicin, Delavirdine, delphinidin, delta-1-pyrroline-5-carboxylate, delta8-THC, Denagard, denbinobin, denosumab, deoxyhypusine, deoxyverrucosidin, Depas, dephosphonocalyculin A, Deproceptin, deramciclane, dermorphin, desethylchloroquine, desloratadine, desmethylazelastine, Desmethyldeprenyl, desmethyl-tamoxifen, DEVD-CHO, dexecadotril, dexloxiglumide, Dextropropoxyphene, Diaben, Diacomit, diadenosine tetraphosphate, Didanosine, dillapiol, Diltiazem, Dinoprostone, Diosgenin, diosmetin, dioxirane, Dioxolan, Dipyrone, Disopyramide, Ditiocarb, Dizocilpine Maleate, DNSC1, Doca, dofequidar, Dolomin, Domperidone, Doxazosin, doxifluridine, Doxycycline, DPC 681, DPCPX, DPPH, Droxia, Drysol, duloxetine, Durapatite, Dursbanoxon, DX 9065a, Dxms, dynapen, Dynatra, dynorphin, dysidenin, dysprosium, dystrobrevin, E 10, EACA, ebastine, ebrotidine, Econ, econazole, ecteinascidin 743, ectoine, Edex, Edrophonium, efavirenz, efrapeptin, EGCg, EGRck, EHT 1864, eletriptan, Embelin, embellistatin, EMD 53998, EMD 61753, emetine, E-MIX 80, Emodin, Empecid, emtricitabine, enadoline, Enalapril, Enalaprilat, Enediynes, Enelone, Enoximone, EPIB, Epicar, epicatechin gallate, epimedin C, Epoprostenol, Epostane, Epothilones, epoxybergamottin, epsilon-viniferin, eptifibatide, ergotamine, eriocalyxin B, erlotinib, erucin, Eryc, Eskazine, Estramustine, ET18-Ome, Etfc cpd, Ethacrynic Acid, Ethambutol, Etidronic Acid, Etodolac, Etoposide, etoricoxib, Etorphine, etravirine, Eufor, eumelanin, eupatilin, everolimus, Evex, Evodin, exenatide, Extina, ezetimibe, F 11440, Fanchinine, F-Ara-A, febuxostat, felbamate, Felodipine, fenitrothion, fenofibric acid, Fenoprofen, Fenretinide, fexofenadine, fingolimod, fipronil, fisetin, FLCZ, Flecamide, Flesinoxan, flibanserin, Floxacillin, Fludeoxyglucose F 18, Flunarizine, fluorexon, Fluorouracil, Fluparoxan, Flupenthixol, fluvoxamine, fondaparinux, Fonofos, Format, Forskolin, fosamprenavir, Foscarnet, Frakefamide, fucoidan, fulvestrant, Fura-2, furafylline, Furylfuramide, FYDE, Gambogic acid, gedunin, gefitinib, Geldanamycin, Gemfibrozil, genipin, Gentamicins, gepirone, Gestodene, GF 120918, GGTI 298, GI 129471, Ginkgo-biloba-extract, glabridin, GLCa, Glumin, Glycyron, glyox, Gnidimacrin, gossypetin, gossypol, GR 113808, grifolin, Grofo, Guggulsterone, gusperimus, Harzol, Hbim, HESPERETIN, Hexadimethrine, HMBA, hypsiziprenol A9, hypusine, hyrtioerectine A, ibandronic acid, IBMX, I-BOP, Ibotenic Acid, Icosapent, ICRF 193, idebenone, IDN 5390, Ifosfamide, Ifosfamide, IGF-1, Iloprost, imatinib, imidafenacin, imperatorin, Impulsin, Imrecoxib, Imutex, indazole, Indinavir, indiplon, indirubin-3′-monoxime, infliximab, inogatran, Ipral, Iprivask, ipsapirone, irbesartan, Iressa, irinotecan, irisolidone, irofulven, Irox, Ismo, Isobac, isochaihulactone, Isodonol, isoflavone, Isorhamnetin, isosteviol, Isradipine, Istidina, ITF 2357, Itraconazole, Ivermectin, ixabepilone, J 113397, J 113397, jasplakinolide, juglone, juzentaihoto, K 252, kaempferol, KAFA, kahweol, Kainic Acid, kamiuntan-to, Kaolin, KB 2796, K-DR, Keloid, Kemi, ketazocine, Ketopgflalpha, KKHA-761, KN 62, KN 93, KNK 437, KP372-1, K-PAM, KPMK, KR 31831, KRM 1648, K-SR, kurarinone, KYNA, L 685458, L797591, LAGA, Lamivudine, lamotrigine, lanreotide, lapachenole, lapatinib, LAQ824, laquinimod, latrunculin A, LBH589, leflunomide, lenalidomide, Lendorm, Lentinan, Leukotriene B4, Leukotriene C4, Leukotriene D4, leukotrienes, Levonorgestrel, liarozole, lintopride, liquiritin, LMWH, LNAC, lonafarnib, lonidamine, Loperamide, lopinavir, Lopril, Loratadine, Lorazepam, Lorex, Losartan, Lovan, loxiglumide, L-T3, lupeol, luteolin, lutetium, Lutex, LY 117018, LY 293111, LY 293284, LY 303511, LY231514, mahanine, Maleimides, Malix, manzamine A, maraviroc, MBC1, MCYST-LR, Mebumal, Medemycin, Medroxyprogesterone 17-Acetate, Melatol, meletin, melitten, meloxicam, Memantine, Menatetrenone, MENT, Mephenyloin, Meprobamate, MeSAdo, mesalamine, Mesaton, mesoglycan, Mesol, metazachlor, Meth, methanopterin, Methorphan, Methoxsalen, methoxymorphinan, Methylprednisolone, Methylthioinosine, Metkephamid, Metopiron, Metribolone, Miazine, miconazole, Mictonorm, Midazolam, Mifepristone, miglustat, milbemycin, Mimosine, mirtazapine, Mit-C, mithramycin A, Mitoxantrone, MK-0524, MLN 944, Molsidomine, Monensin, monocillin I, monodansylcadaverine, mono-N-demethyladinazolam, Monorden, MORIN, morphine-3-glucuronide, mosapride, motapizone, Motuporin, moxifloxacin, MRK 003, MTPA, Muran, Muscarine, N-(4-aminophenethyl)spiroperidol, N-(4-aminophenyl)maleimide, N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine, N-(8-amino-1-carboxyoctyl)-alanyl-proline, N(alpha)-(4-amino-4-deoxypteroyl)N(delta)-hemiphthaloyl-L-ornithine, N-(m-heptyl)-5-chloro-1-naphthalenesulfonamide, N-3-isoquinolinyl-2-((4-pyridinylmethyl)amino)benzamide, NABU, Naftalen, Naloxone, Naltrexone, naltrindole, NAN-190 hydrobromide, nanchangmycin, Naphazoline, NARIGENIN, nateglinide, N-benzyloxycarbonylprolylprolinal, N-dehydroxyzileuton, N-desmethylclobazam, nedaplatin, Nefazodone, Nelfinavir, nemonapride, neodymium, Neomycin, N-ethylmaleimide, netoglita zone, neuromedin C, Neut, Nevirapine, Niacinamide, nicaraven, Nicardipine, Niceritrol, Nigericin, niguldipine, Nimodipine, NK 104, NMDA, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide, NN 703, Nobiletin, NOC 18, Nociceptin, noralfentanil, Norbinaltorphimine, norcantharidin, Nordihydroguaiaretic Acid, Norethindrone, noreximide, norfluoxetine, norlaudanosoline, Nortilidine, norverapamil, novobiocin, NPI 031L, NRDC, NSC 23766, NSC 295558, NSC 366140, NSC 663284, N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide, NU2058, NU6102, nutlin 3, NVP-AEW541, obovatol, OC 144-093, ochratoxin A, Octreotide, Octreotide, O-demethyltramadol, Odesethylreboxetine, oenothein B, Ogen, OH-pro, Oktan, Olamine, olanzapine, oleandrin, oleylamide, olmelin, olomoucine, Olymp, omalizumab, omapatrilat, omega-N-Methylarginine, Omeprazole, omeprazole sulfone, Ondansetron, ONO 1301, Optef, Org 31540, Orphenadrine, OSI 930, OSU 03012, Ouabain, ovalicin, Ovex, oxaliplatin, oxatomide, oxcarbazepine, Oxidopamine, oxymatrine, Oxytrol, Paclitaxel, palytoxin, pamidronate, p-Aminohippuric Acid, panaxadiol, pantoprazole, PAPP, Parthenolide, Patulin, pazopanib, PCSO, PD 169316, PD 173074, PD 98059, PDBU, Pectenotoxin II, pegvisomant, Pemetrexed, pentosidine, Pentoxifylline, Peplomycin, Pepstatin A, Perazine, Perillol, Perindopril, perylene bisimide, phen, phen, phenanthrene, phenothiazines, Phenprocoumon, Phenyloin, pheophorbide a, phloretin, Picibanil, picric acid, picropodophyllin, pidotimod, pifithrin, pindobind, pioglitazone, Piroxicam, plumbagin, Pluronic p 85, PMPA, PMSF, posaconazole, PP-IX, Pragmoline, Pravastatin, Prazosin, PRDL, Prednisone, preussin, Primidone, Proadifen, Procasil, Procetofen, Prodigiosin, Prodix, Promegestone, Propofol, prostaglandin A1, prostaglandin D2, prostaglandin E1, prostaglandin F2alpha, prostaglandin H2, prostaglandin J2, prostaglandins, prostaglandins G, prostratin, prucalopride, prunustatin A, Pseudohypericin, pseudolaric acid B, psilocybin, Psoralens, PTAP, PTX-B, puerarin, Pugnac, p-XSC, Pyrethrins, pyrvinium, quercitrin, quetiapine, Quicifal, quinupristin-dalfopristin, R 101933, rabeprazole, radester, Raloxifene, ramiprilat, rebamipide, reboxetine, remifentanil, renzapride, repaglinide, Requip, Revex, Rhodinal, Riacon, Ribavirin, Rifabutin, Riluzole, rimorphin, risedronic acid, risperidone, Ritodrine, Ritonavir, rituximab, RMI 12330A, Ro 13-8996, Ro 64-0802, Robitet, Rolipram, romidepsin, ropivacaine, Roquefortine, roscovitine, rosiglitazone, rosmarinic acid, rosuvastatin, Rozevin, RPR 121056, Rulid, rutecarpine, Rutin, S17092-1, S 9788, S azabisabolene, Safingol, SAHA, saintopin, Salicin, salinomycin, salinosporamide A, salubrinal, salvin, salvinorin A, samarium, sampatrilat, sangivamycin, Saquinavir, Sarasar, sarizotan, SB 203580, SB 207266, SB 216763, SB 225002, SB 415286, SB-649915, SB-706375, SCH 66712, schizandrin B, SCIO-469, scoparone, Sediel, selamectin, Selegiline, Serad, sesamin, sevoflurane, Sildenafil, silybin, Sizofuran, sofalcone, sorafenib, SP 100030, sparfloxacin, spiradoline, spiraprilat, spirogermanium, SR 48692, SR 59230A, SR163-154, SRIH, ST 1481, STA 5326, stachybotrydial, Stanozolol, Stavudine, SU 1498, SU 5416, SU 5614, SU 6656, SU 6668, SU 9516, Sucralfate, Sufentanil, Sulem, Sulfamerazine, Sulfamethazine, sulfamide, Sulfaphenazole, Sulfoximine, Sulindac, sultopride, Sumatriptan, sunitinib, sural, T 0901317, TAC 101, Tacrolimus, Tamogel, tamsulosin, tandospirone, Tangeretin, tanshinone, tariquidar, Taseron, Taurolin, TAXOTERE, tazarotene, TBDZ, TBHQ, TCDD, Tegafur, tegaserod, telithromycin, telmisartan, temozolomide, temsirolimus, Teniposide, Terfenadine, Teriparatide, Tetraprenol, TG101209, thalicarpine, Thapsigargin, Theaflavin, Thiazolidinediones, thiocoraline, thioridazine, Thiorphan, thromboxane B2, thulium, thymalfasin, Thymopentin, thymoquinone, Ticlopidine, Tilidine, tipifarnib, tipranavir, tirilazad, TKI-31, Tmndga, TMPN, Toddalin, Todralazine, tofisopam, Tolterodine, topiramate, Topotecan, Toremifene, Toxaphene, Tramadol, Tramat, trandolapril, Trapidil, trapoxin A, trastuzumab, Trazodone, Tremode, triazolam, triazolobenzodiazepines, tributylstannane, trichostatin A, trichostatins, Trifluoperazine, trioctyl phosphine oxide, Triolein, triptolide, TRK 820, troglitazone, Troleandomycin, tropisetron, Trospium chloride, Tunicamycin, tylophorine, Tylox, tyrphostin AG-490, tyvelose, U 0126, U 69593, Ubizol, UH 301, Usaf B-12, USAN, Valproic Acid, valsartan, valspodar, vandetanib, vapreotide, venlafaxine, Verapamil, verlukast, verrucosidin, versipelostatin, VGA1155, Vigil, vincaleukoblastine, vincristine, Vindesine, vinorelbine, Visken, Viviq, voriconazole, vorozole, vulnibactin, Wakil, Warfarin, Wartmannin, WAY 100635, Wogonin, WR 1065, WS 79089B, xanthohumol, Xaxa, ximelagatran, Xylit, Y 27632, YM-201627, YM-231146, zacopride, zafirlukast, ZD 4190, zeaxanthin, Zeldox, zileuton, Zimco, zincov, ZK 112993, ZM323881, zopiclone, ZSTK474, Zymosan, or a combination thereof. These compounds interact with newly identified key regulators of fat deposit functions, triglyceride circulation and obesity. Mechanistically the inventive treatments involves the modulation of the genes and gene function or interaction with the gene products, in particular proteins, of the genes listed in table 1.

According to the investigation described herein it was found that these compounds modify at least one gene selected from the drosophila genes CG30184, CG10369, CG32401, CG2374, CG8693, CG14909, CG13299, CG7847, CG30462, CG30462, CG15169, CG1650, CG6577, CG30491, CG4373, CG10407, CG2198, CG6356, CG5744, CG9506, CG31169, CG1728, CG9220, CG15625, CG5550, CG13088, CG13188, CG14968, CG1503, CG1666, CG14869, CG2702, CG2984, CG4394, CG9922, CG14529, CG17781, CG17781, CG9153, CG15178, CG5641, CG3879, CG15579, CG1422, CG6299, CG8107, CG7103, CG10617, CG30360, CG32971, CG32336, CG31036, CG12602, CG9676, CG1433, CG1100, CG31697, CG7095, CG2165, CG10230, CG10916, CG3274, CG18767, CG5072, CG3396, CG15582, CG16826, CG6788, CG9487, CG1888, CG4637, CG15162, CG5719, CG2254, CG4695, CG14936, CG17867, CG15646, CG5402, CG15095, CG8250, CG18030, CG14303, CG14164, CG14677, CG12105, CG17440, CG32459, CG11404, CG8954, CG13138, CG9056, CG12997, CG12997, CG5436, CG14330, CG10809, CG1622, CG3893, CG1112, CG31690, CG12664, CG13679, CG17556, CG10062, CG31744, CG9760, CG1555, CG14375, CG32170, CG4271, CG32234, CG7287, CG14341, CG30486, CG31692, CG31421, CG5467, CG30065, CG9086, CG1688, CG17026, CG4415, CG10343, CG15388, CG13984, CG3313, CG13116, CG4662, CG6919, CG17841, CG30411, CG9053, CG1180, CG14166, CG13125, CG13344, CG1490, CG2867, CG5591, CG14362, CG1531, CG15390, CG6689, CG14234, CG14265, CG5674, CG3917, CG8257, CG9028, CG1722, CG18402, CG7082, CG11797, CG3663, CG16704, CG31172, CG31219, CG1363, CG6721, CG5688, CG8527, CG13137, CG6612, CG6947, CG7737, CG1705, CG14704, CG10300, CG3597, CG3425, CG2540, CG6856, CG12259, CG4583, CG3843, CG9634, CG3809, CG9295, CG9485, CG11555, CG11601, CG14095, CG10166, CG2852, CG14164, CG14164, CG2898, CG3162, CG6603, CG8721, CG17742, CG14127, CG8665, CG9438, CG32113, CG32353, CG4957, CG33558, CG11570, CG32669, CG11575, CG30271, CG7830, CG31061, CG2076, CG17596, CG6824, CG17921, CG12875, CG13020, CG13972, CG13673, CG10772, CG8079, CG13127, CG9144, CG8979, CG7097, CG11768, CG10632, CG14903, CG1874, CG33466, CG3367, CG4851, CG17985, CG31229, CG3260, CG13023, CG11125, CG17184, CG31812, CG13360, CG30075, CG30183, CG7485, CG5495, CG5495, CG7065, CG13202, CG7779, CG9322, CG7091, CG16758, CG5071, CG4920, CG1516, CG9554, CG10101, CG3004, CG7796, CG10152, CG18741, CG8444, CG11425, CG10128, CG10542, CG11878, CG14434, CG12345, CG2091, CG31459, CG13319, CG7177, CG7776, CG15005, CG31605, CG7213, CG17283, CG18268, CG3017, CG7567, CG32091, CG9695, CG8222, CG1515, CG8256, CG1975, CG32467, CG3817, CG4038, CG6193, CG1572, CG8117, CG3526, CG7099, CG18525, CG9198, CG30470, CG17273, CG31439, CG1387, CG9952, CG6580, CG10840, CG13221, CG8202, CG8786, CG7199, CG11663, CG12683, CG31161, CG8009, CG17202, CG1683, CG17335, CG33204, CG14694, CG11229, CG16836, CG12209, CG18414, CG13475, CG11621, CG13332, CG11756, CG11133, CG18586, CG4944, CG3213, CG4152, CG6147, CG8515, CG5827, CG12691, CG8308, CG13807, CG2260, CG30004, CG4247, CG4247, CG5739, CG4202, CG4264, CG5245, CG13707, CG3523, CG10686, CG9565, CG4111, CG14673, CG31132, CG5355, CG32149, CG8443, CG17461, CG8190, CG13744, CG9258, CG6043, CG1759, CG8534, CG14792, CG8451, CG8654, CG12806, CG14938, CG9399, CG10542, CG13168, CG31845, CG6277, CG17819, CG2818, CG1688, CG13868, CG17736, CG7546, CG31693, CG12897, CG2146, CG3440, CG3696, CG12426, CG18319, CG18279, CG18279, CG3054, CG2145, CG3825, CG9781, CG13423, CG12030, CG14911, CG3911, CG6122, CG7206, CG8566, CG30476, CG9470, CG6127, CG5381, CG12505, CG1279, CG32140, CG12184, CG31364, CG1963, CG5484, CG4634, CG9748, CG32442, CG1921, CG18740, CG1242, CG9946, CG11121, CG3497, CG6817, CG30080, CG1171, CG11430, CG10691, CG13281, CG11352, CG3839, CG14368, CG14024, CG9936, CG11505, CG11906, CG1263, CG14011, CG11339, CG12015, CG30389, CG17331, CG15432, CG15507, CG14842, CG3906, CG17754, CG5289, CG5378, CG5625, CG6156, CG13243, CG8239, CG1821, CG7762, CG3108, CG8053, CG3605, CG4207, CG8431, CG9098, CG5270, CG5595, CG6064, CG6967, CG7134, CG7549, CG6892, CG10687, CG10712, CG11981, CG12770, CG15599, CG18563, CG7770, CG6322, CG3806, CG3980, CG6054, CG7292, CG3992, CG2998, CG8337, CG13194, CG5147, CG16903, CG11202, CG10084, CG12323, CG31484, CG6949, CG7352, CG10728, CG11376, CG32210, CG7109, CG8615, CG9160, CG8298, CG15115, CG1965, CG12595, CG15321, CG6009, CG11267, CG4453, CG3971, CG17255, CG32791, CG14016, CG14016, CG1740, CG32667, as well as their human orthologues. According to the present invention function of at least one of these genes is modified by the inventive compounds, in particular the small molecules given in table 1. In preferred embodiments the compound modulates at least two, three, four, five or six or more of these genes (or orthologues). Further compounds suitable to modulate gene function include the administration of therapeutic proteins or nucleic acids, such as transgenes or inhibitory nucleic acids (RNAi molecules, siRNA, antisense RNA or DNA). Such interfering nucleic acids bind messages of the genes leading to degradation and reduced gene expression. Preferred therapeutic proteins include the gene products of these genes (as agonists) or antibodies which specifically bind these proteins (as antagonists, but also as agonists if protein activity is increases—such as by binding and blocking an inhibitor binding site). The inventive compounds can act as either agonist by increasing the gene function (via mRNA regulation or interaction with the protein) of a protein in the enzymatic pathway of any one of the above listed genes or an antagonist in said pathways. The antagonizing or activating (agonist) activity of the compounds acts preferably on the identified obesity genes (including their gene product) themselves or on a binding partner thereof. In preferred embodiments antagonists of the obesity genes are used.

Among the genes that can be targeted are also potential regulators of feeding control. For instance, odorant receptor genes 10a, 56a, 65a, 67a, 83cd, CG10407 and gustatory receptors 98b and 36b can be targeted, in particular, suppressed or antagonized. Also, the dopamine receptor DopR2, two octopamine receptors (TyrR and oa2) and the Nmda-receptor associated protein Nmda1 In addition, altered fat deposition was observed in response modification of genes involved in glucose/lipid mobilization including fructose-1,6-bisphosphatase (fbp), the two members of the glycerol phosphate shuttle (CG31169 and Gpo-1), mitochondrial acyl-carrier protein 1 (mtacp1), ADP/ATP translocase 2 (Ant2), pyruvate carboxykinae (CG1516), and fatty-acid synthetase (fasn). Further examples of genes to be modified according to the present invention includes the Drosophila orthologues of glucagon (akh), the insulin receptor (dInR), as well as the downstream kinases PI3-kinase (dPI3K), ribosomal-S6-kinase (dRSK), the CREB-coactivator dTORC, and the critical TOR-signaling constituent dTSC-1, Drosophila homologues of the critical early adipogenic regulators NCOR1/2, Jag1/2, and TAK1, or the metabolic regulators CRTC1/2 and pyruvate carboxylase (PC). To all of the drosophila genes the present invention has identified human orthologs (table 1) that can be targeted by the inventive use of the therapeutic compounds.

According to the present invention all genes listed in table 1, those shown in example 1.2, in particular those illustrated in examples 1.3, 1.4 or 1.5, can be modified by therapeutic administration of suitable compounds. Preferred genes to be modified according to the present invention are those discussed above, as well as the LSD (Lipid Storage Droplet) and LPD (LiPid Depleted) genes, the Drosophila insulin like peptides (lip's), the glucagon homologue akh and its receptor akhr, as well as adipose (adp), bubblegum (bbg), and the Drosophila SREBP homologue, HLH106, CG8451, of course, as well as their human orthologues.

TABLE 1 List of therapeutic compounds: Small Molecule: name of compound (see list of synonyms below), Human ortholog: human gene name of therapeutic target, Human Entrez ID: gene ID, Drosophila: ortholog Drosophila gene ID, Type: Type of interaction Molecule (O: Obesity - obesity pathway interaction, B: validated binding partner) Small Molecules Human Orthologs Human Entrez ID Drosophila Type (5-(2- CYP3A4 1576 CG9438 O methoxy-5- chloro-5- phenyl)furan- 2- ylcarbonyl)guanidine (E)-4-(2-(2- ABCB1 5243 CG3879 O (N-acetyl-N- (4- methoxybenzenesulfonyl)amino) stilbazole))1-oxide (melle- FK6 8468 CG375 O 4)cyclosporin 1-(1- CYP3A4 1576 CG9438 O cyclohexylethylamino)- 4- phenylphthalazine 1-(2- HTR1A 3350 CG7485 O methoxy- phenyl)-4-(4- (2- phthalimido)butyl)piperazine 15- JUN, JUND, FLT1, KDR, 3725, 3727, 2321, 3791, CG2275, CG2275, CG8222, O deoxyprostaglandin TFDP2, JUNB, APC, HGF 7029, 3726, 324, CG8222, CG4654, J2 3082 CG2275, CG6193, CG13744 17- CDK6, HSP90AA1, CDK4, 1021, 3320, 1019, 3308, CG5072, CG1242, CG5072, O (allylamino)- HSPA4, DNAJB1, CCND1, 3337, 595, 3791, CG6603, CG10578, 17- KDR, EIF2S1, ABCB1 1965, 5243 CG9096, CG8222, CG9946, demethoxy- CG3879 geldanamycin 17- HSPH1, HSPA4, DNAJB1, 10808, 3308, 3337, 2247, CG6603, CG6603, CG10578, O (dimethylaminoethyl- FGF2, HSP90AA1 3320 CG4608, CG1242 amino)-17- demethoxy- geldanamycin 1-aminooxy-3- ODC1 4953 CG8721 O aminopropane 1-beta-D- JUN 3725 CG2275 B arabinofuranosyl- Cytosine 1-carbamoyl- PSMD2 5708 CG7762 O 4- phenylpyrrolidone-2 1- GLA 2717 CG5731 B Carboxyglutamic Acid 1- GLA 2717 CG5731 B deoxygalactonojirimycin 1- CYP3A4 1576 CG9438 O hydroxy- methylmidazolam 2-[2-[2-[2- MME 4311 CG9565 O [2-amino-3- (4- hydroxy- phenyl)-1- oxo- propyl]amino- 1-oxo- ethyl]amino- 1-oxo- ethyl]amino- 1-oxo-3- phenyl- propyl]amino- 4-methyl- pentanoic acid 25- CYP3A4 1576 CG9438 O desacetylrifabutin 2-AAF RAC1 5879 CG2248 B 2-AAF ABCB1 5243 CG3879 O 2-AG RAC1 5879 CG2248 B 2-AG FAAH 2166 CG6007 B 2-AP PLG 5340 CG13744 O 2- HSPA5, ABCB1, FGF2 3309, 5243, 2247 CG5436, CG3879, CG4608 B cyclopentyl- 5-(5- isoquinolyl- sulfonyl)-6- nitro-1H- benzo(D)imidazole 2-DG CCND1, CCNB1, CDK4 595, 891, 1019 CG9096, CG3510, CG5072 O 2-hydroxy-1- CCND1 595 CG9096 B naphthylaldehyde isonicotinoyl hydrazone 2- CYP3A4 1576 CG9438 O methoxyacetic acid [2-[2- [3-(1H- benzoimidazol- 2- yl)propyl- methyl- amino]ethyl]- 6-fluoro-1- isopropyl- tetralin-2- yl] ester 2- FGF2 2247 CG4608 B methylarachidonyl- 2′- fluoroethylamide 2-phenyl-4- CDC2 983 CG5363 B oxohydroquinoline 2- ABCB1 5243 CG3879 O propylquinoline 3-(5-((4- KDR 3791 CG8222 O (methylsulfonyl)- 1- piperazinyl)methyl)- 1H-indole-2- yl)quinolin- 2(1H)-one 3-AB JUND, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2275 B 3′-deamino- ABCB1 5243 CG3879 O 3′- hydroxy- doxorubicin 3-HF ABCB1 5243 CG3879 O 3- CYP3A4 1576 CG9438 O Methoxyoestradiol 3-MF OPRM1 4988 CG7285 B 4-(4-(1- KDR 3791 CG8222 O Amino-1- methylethyl)phenyl)- 2-(4-(2- morpholin-4- yl- ethyl)phenylamino)pyrimidine- 5- carbonitrile 4′- CSE1L, ABCB1 1434, 5243 CG13281, CG3879 O epidoxorubicin 4-methyl-N- CYP3A4 1576 CG9438 O (3-(4- methylimidazol- 1-yl)-5- (trifluoro- methyl)phenyl)- 3-((4- pyridin-3- ylpyrimidin- 2- yl)amino)benzamide 4′-N- CDK2 1017 CG5363 B benzoyl- staurosporine 4PBA HSPA8, HSP90B1, HSPA5 3312, 7184, 3309 CG31449, CG1242, CG5436 O 4-PCB CYP24A1 1591 CG6042 B 5-(4′-(N- CDK2, CCNA2 1017, 890 CG5363, CG3510 B piperidinyl)phenylazo)indazole 5-bromo-4- CYP3A4 1576 CG9438 O chloro-3- indolyl beta- galactoside 5- HTR1A 3350 CG7485 O carboxamidotryptamine 5- METAP2 10988 CG4008 B demethylovalicin 5′-O-(((2- FYN 2534 CG7524 B decanoylamino- 3- phenylpropyloxycarbonyl) amino)sulfonyl)uridine 6′-N- FBN2 2201 CG3936 B methyl- sisomicin 7 HC CCND1 595 CG9096 B 7,8-BF CYP3A4, CYP3A7 1576, 1551 CG9438, CG9438 O 7C3MT GORASP1, CYP3A4 64689, 1576 CG7809, CG9438 O 7- CDK4, CDK2, CDK6, CDC2, 1019, 1017, 1021, 983, CG5072, CG5363, CG5072, B hydroxystaurosporine ABCB1, PDPK1, CCNA2 5243, 5170, 890 CG5363, CG3879, CG1210, CG3510 7- GORASP1, DYNLL1 64689, 8655 CG7809, CG5450 B ketocholesterol 8-Hydroxy-2- HTR1A 3350 CG7485 O (di-n- propylamino)tetralin 8- RPS3, CDK4 6188, 1019 CG6779, CG5072 O hydroxy- guanosine 9-(2-hydroxy- CCND1 595 CG9096 B 3- nonyl)adenine 9-beta-D- MTAP 4507 CG4802 B erythrofuranosyladenine 9-CRA FBN2, JUND, JUNB, HSPA4, 2201, 3727, 3726, 3308, CG3936, CG2275, CG2275, B JUN, CCND1, CYP27B1, 3725, 595, 1594, CG6603, CG2275, CYP24A1 1591 CG9096, CG6042, CG6042 9-hydroxy- CYP4F3 4051 CG3466 B risperidone A-300-I JUNB, CDK4, JUND, NCOR1, 3726, 1019, 3727, 9611, CG2275, CG5072, CG2275, O DOCK8, OPRM1, EGR1, 81704, 4988, 1958, CG7951, CG11376, ABCB1, CCND1, JUN, 5243, 595, 3725, 2626 CG7285, CG7847, CG3879, GATA4 CG9096, CG2275, CG3992 a-ADP PLAT 5327 CG13744 O AAL 881 KDR 3791 CG8222 O AATP CYP3A4, CYP4F3, RAC3 1576, 4051, 5881 CG9438, CG3466, CG2248 B AB 2 GLA, JUN 2717, 3725 CG5731, CG2275 B abacavir KLHL1, HSPA4, ABCB1 57626, 3308, 5243 CG17754, CG6603, CG3879 O Abufene ECE1 1889 CG9565 O Acenocoumarol NF2 4771 CG14228 B Acetidin ABCB1, SERPINB1 5243, 1992 CG3879, CG9456 B Acetorphan MME 4311 CG9565 O acetoxy- EGR1 1958 CG7847 O methyl-ester Aclarubicin MYB 4602 CG9045 B ACNU ABCB1 5243 CG3879 O Acolen CYP3A4 1576 CG9438 O ACON CYP3A4, SF4, CCND1, 1576, 57794, 595, 5243, CG9438, CG31550, CG9096, O ABCB1, ABCB4 5244 CG3879, CG3879 actein CCND1, CDK4 595, 1019 CG9096, CG5072 O acteoside CCND2, CCND1, CCND3 894, 595, 896 CG9096, CG9096, CG9096 B Actihaemyl PCSK5 5125 CG10772 O Actosin PDGFB 5155 CG7103 O adalimumab PSMD12 5718 CG1100 O Adanon ABCB1, OPRM1, CYP3A4 5243, 4988, 1576 CG3879, CG7285, CG9438 O ADMA KDR 3791 CG8222 O ADMA HSP90AA1 3320 CG1242 O Adofeed SLC5A8, PLG, SLC5A12 160728, 5340, 159963 CG32669, CG13744, CG32669 O Adrenor RAC1, TBXAS1, JUND, 5879, 6916, 3727, 5155, CG2248, CG3466, CG2275, B PDGFB, HSPB6, JUNB, 126393, 3726, 3082, CG7103, CG4183, HGF, FYN, MYH7, JUN 2534, 4625, 3725 CG2275, CG13744, CG7524, CG2146, CG2275 Adrin CCNE2, RAC1, FOXD3, 9134, 5879, 27022, 3320, CG3938, CG2248, CG3668, B HSP90AA1, CCND1, ECE1, 595, 1889, 5243, CG1242, CG9096, ABCB1, PLAT, OPRM1, 5327, 4988 CG9565, CG3879, CG13744, CG7285 AEBSF PLG, HSPA5, NCOR1 5340, 3309, 9611 CG13744, CG5436, CG7951 B AEE 788 KDR 3791 CG8222 O AG 1879 KDR 3791 CG8222 O ajoene CCNB1 891 CG3510 B Aklavin QRSL1 55278 CG6007 B alachlor CYP3A4, CYP3A7 1576, 1551 CG9438, CG9438 O Alat CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O ALDA PSMD2 5708 CG7762 O Aldara TSC1 7248 CG6147 O Aldocorten SER- 462, 27022, 3480, 9068, CG9456, CG3668, CG1842, B PINC1, FOXD3, IGF1R, 65125, 65266, 1357, CG5550, CG7177, ANGPTL1, WNK1, WNK4, 1958, 4051 CG7177, CG14820, CG7847, CPA1, EGR1, CYP4F3 CG3466 alemtuzumab CCND2 894 CG9096 B Alendronate CYP27A1, BEST1 1593, 7439 CG6042, CG6264 B Alfarol BEST1 7439 CG6264 B Alfentanil OPRM1, CYP3A4 4988, 1576 CG7285, CG9438 O ALIMTA TBXAS1 6916 CG3466 B aliskiren MAPT, ATP6AP2, CYP3A4 4137, 10159, 1576 CG31057, CG8444, CG9438 O Alli CPB2 1361 CG14820 B Allnal HSPA4 3308 CG6603 O allylamino- HSP90AA1 3320 CG1242 O demethoxy- geldanamycin alpha- OPRK1 4986 CG7285 B neoendorphin alternagin-C KDR 3791 CG8222 O Alvesco CYP3A4 1576 CG9438 O alvimopan OPRM1 4988 CG7285 B Am 80 JUNB, JUN, JUND 3726, 3725, 3727 CG2275, CG2275, CG2275 B Amatin SMARCA4, SMARCA2 6597, 6595 CG5942, CG5942 B AMCHA PLG 5340 CG13744 O AMD 070 CYP3A4 1576 CG9438 O amentoflavone GORASP1 64689 CG7809 B Amiloride CCNB1, PDPK1, ODC1, 891, 5170, 4953, 5340 CG3510, CG1210, CG8721, O PLG CG13744 Amine BB SERPINB1 1992 CG9456 B Amiodarone SLC5A8 160728 CG32669 O Amiodarone SLC5A8, CYP3A4 160728, 1576 CG32669, CG9438 O amlexanox FGF1 2246 CG4608 B Amlodipine PLAT, CYP3A4, JAK2, 5327, 1576, 3717, 595, CG13744, CG9438, CG1594, O CCND1, ABCB1 5243 CG9096, CG3879 Ammo MBL2 4153 CG7763 B Ampicillin PLG 5340 CG13744 O amprenavir ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O amrubicin ABCB1 5243 CG3879 O AMSA TOP2B 7155 CG10223 B amsonic acid CDC2 983 CG5363 B Anaboleen CYP24A1, SNAI2, CYP27B1, 1591, 6591, 1594, 5243, CG6042, CG3758, CG6042, B ABCB1, CCND1, 595, 2252, 890, 3480, CG3879, CG9096, FGF7, CCNA2, IGF1R, 3725 CG4608, CG3510, CG1842, JUN CG2275 Anandamide CDK2, HTR1A, FAAH 1591, 6591, 1594, 5243, CG6042, CG3758, CG6042, B 595, 2252, 890, 3480, CG3879, CG9096, 3725, 1017, 3350, CG4608, CG3510, CG1842, 2166 CG2275, CG5363, CG7485, CG6007 Anco ABCB1, CYP27A1, GORASP1, 5243, 1593, 64689, 3312, CG3879, CG6042, CG7809, B HSPA8, MAPT 4137 CG31449, CG31057 and- CCND1 595 CG9096 B carboxyfluorescein- diacetate- succinimidyl- ester Andros- KSR1 8844 CG2899 B tenediol anilinyl FLT1 2321 CG8222 O Anisomycin JUN, PSMD12, EGR1 3725, 5718, 1958 CG2275, CG1100, CG7847 O ANSA HSP90AA1 3320 CG1242 O antibiotic G HSPB2, CCNA2, HSPB1 3316, 890, 3315 CG14207, CG3510, CG14207 B 418 antibiotic PSMD12 5718 CG1100 O H107 antineoplaston ATF2, MAPT, JUN, PDCD2, 1386, 4137, 3725, 5134, CG30420, CG31057, CG2275, O A10 GSK3B, ABCB1, GLA, 2932, 5243, 2717, CG326, CG2621, MAGT1, HGF 84061, 3082 CG3879, CG5731, CG7830, CG13744 Antizol P11 8909 CG2145 O APAP CYP3A4 1576 CG9438 O APDC MAGT1, JUNB, HGF, JUN, 84061, 3726, 3082, 3725, CG7830, CG2275, CG13744, B DNAJB1, IGF1R, GORASP1, 3337, 3480, 64689, CG2275, CG10578, ABCB1, JUND 5243, 3727 CG1842, CG7809, CG3879, CG2275 Aphidicolin POLS 11044 CG11265 B Aphidicolin POLS, JUN 11044, 3725 CG11265, CG2275 B Aphloiol GORASP1 64689 CG7809 B apicidin ABCB1, CDK2, CDK4, CCND1, 5243, 1017, 1019, 595, CG3879, CG5363, CG5072, B CCND3 896 CG9096, CG9096 Apigenin CDC2, ABCB1, JUNB, JUN, 983, 5243, 3726, 3725, CG5363, CG3879, CG2275, B GORASP1, CCND1, 64689, 595, 3727, CG2275, CG7809, JUND, FBRS, CDK4, CDK2, 64319, 1019, 1017, 890, CG9096, CG2275, CG9056, CCNA2, HGF, CCNB1 3082, 891 CG5072, CG5363, CG3510, CG13744, CG3510 aplidine JUNB, JUN, RAC1, CYP4F3, 3726, 3725, 5879, 4051, CG2275, CG2275, CG2248, B CYP3A4, JUND 1576, 3727 CG3466, CG9438, CG2275 aprepitant CYP3A4 1576 CG9438 O APRL SSTR4, PCSK7, PIK3C2A, 6754, 9159, 5286, 6751, CG7285, CG10772, CG11621, B SSTR1, HTR1A, FYN, 3350, 2534, 1434, CG7285, CG7485, CSE1L, TYK2, JUND, 7297, 3727, 3726, 10988, CG7524, CG13281, JUNB, METAP2, JUN 3725 CG1594, CG2275, CG2275, CG4008, CG2275 Apsor CYP24A1 1591 CG6042 B aptiganel JUN 3725 CG2275 B Aralen NUP214, JUND, ABCB1, 8021, 3727, 5243, 3726, CG3820, CG2275, CG3879, O JUNB, JUN, PLAT 3725, 5327 CG2275, CG2275, CG13744 arctiin CCND1 595 CG9096 B Arecoline CDC2 983 CG5363 B Areether CYP3A4 1576 CG9438 O argatroban SERPINC1 462 CG9456 B aripiprazole HTR1A, CYP3A4 3350, 1576 CG7485, CG9438 O Armor NPDC1 56654 CG30420 B Artein CDK2, LPA, PLAT, CCND3, 1017, 4018, 5327, 896, CG5363, CG13744, CG13744, O ABCB1, CCND1, JUN, 5243, 595, 3725, 8529, CG9096, CG3879, CYP4F2, CYP3A4 1576 CG9096, CG2275, CG3466, CG9438 ASTA CNOT6, SERPINB6, CYP27A1 57472, 5269, 1593 CG31137, CG9456, CG6042 B astatine HSPA4, MAPT, PLAT, SLC5A5 3308, 4137, 5327, 6528 CG6603, CG31057, CG13744, O CG32669 Astemizole CYP3A4 1576 CG9438 O atazanavir CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Atorel HTR1A, SSTR4, SSTR1 3350, 6754, 6751 CG7485, CG7285, CG7285 B atorvastatin RAC1, CYP3A4, SERPINC1, 5879, 1576, 462, 3725, CG2248, CG9438, CG9456, O JUN, CSE1L, ABCB1, 1434, 5243, 3726, CG2275, CG13281, JUNB, JUND, PLAT 3727, 5327 CG3879, CG2275, CG2275, CG13744 Atosil ABCB1 5243 CG3879 O Atovaquone CYP3A4 1576 CG9438 O ATRA PLAT, CCNB1, PAX6, MAPT, 5327, 891, 5080, 4137, CG13744, CG3510, CG11186, O CYP3A7, OPRK1, 1551, 4986, 9611, CG31057, CG9438, NCOR1, KHDRBS1, PSMD6, 10657, 9861, 3315, 6528, CG7285, CG7951, HSPB1, SLC5A5, KDR, 3791, 3726, 894, CG4816, CG5378, CG14207, JUNB, CCND2, MYBL2, 4605, 7155, 1678, 10189, CG32669, CG8222, TOP2B, TIMM8A, THOC4, 2268, 1019, 3727, CG2275, CG9096, FGR, CDK4, JUND, 1593, 2249, 5708, CG9045, CG10223, CG1728, CYP27A1, FGF4, PSMD2, 5718, 462, 5881, 5879, CG1101, CG7524, PSMD12, SERPINC1, 8312, 1017, 983, CG5072, CG2275, RAC3, RAC1, AXIN1, 896, 1103, 1021, 2626, CG6042, CG4608, CG7762, CDK2, CDC2, CCND3, 2247, 3725, 1386, CG1100, CG9456, CHAT, CDK6, GATA4, 324, 595, 5243, 8900, CG2248, CG2248, CG7926, FGF2, JUN, ATF2, APC, 1579, 3082, 2254, 2250, CG5363, CG5363, CCND1, ABCB1, CCNA1, 2200, 64689, 2717, CG9096, CG12345, CYP4A11, HGF, FGF9, 7184, 1580, 1958, CG5072, CG3992, CG4608, FGF5, FBN1, GORASP1, 4311, 2257, 2220 CG2275, CG30420, GLA, HSP90B1, CYP4B1, CG6193, CG9096, CG3879, EGR1, MME, FGF12, CG3510, CG3466, FCN2 CG13744, CG4608, CG4608, CG3936, CG7809, CG5731, CG1242, CG9438, CG7847, CG9565, CG4608, CG555 Auluton MAFB, EGR1 9935, 1958 CG10034, CG7847 O aureobasidin A ABCB1 5243 CG3879 O Aurothioglucose PARD6A, GORASP1 50855, 64689 CG5884, CG7809 B AuTM RAC1, PARD6A 5879, 50855 CG2248, CG5884 B Axert CYP3A4 1576 CG9438 O axitinib KDR 3791 CG8222 O Axsain FOXD3, GORASP1, PLAT, 27022, 64689, 5327, CG3668, CG7809, CG13744, O ABCB1, MAPT, FCN2, 5243, 4137, 2220, 3727, CG3879, CG31057, JUND, JUNB, JUN, MME 3726, 3725, 4311 CG555, CG2275, CG2275, CG2275, CG9565 azacyclonol CYP3A4 1576 CG9438 O Azadc CDK6, DYNLL1, TSC1, 1021, 8655, 7248, 5243, CG5072, CG5450, CG6147, B ABCB1, FYN, ADAMTS1, 2534, 9510, 3728, CG3879, CG7524, JUP, MTAP, RAC2 4507, 5880 CG14869, CG11579, CG4802, CG2248 azamulin CYP3A4 1576 CG9438 O azanediyl ABCB1 5243 CG3879 O group azaspirane FGF2, JAK2 2247, 3717 CG4608, CG1594 B azelastine CYP3A4 1576 CG9438 O azelnidipine JUNB, JUN, CYP3A4, JUND 3726, 3725, 1576, 3727 CG2275, CG2275, CG9438, B CG2275 azidoprazosin ABCB1 5243 CG3879 O Aziran SER- 1992, 2324, 5092 CG9456, CG8222, CG1963 O PINB1, FLT4, PCBD1 Azithromycin JUN, JUND, JUNB 3725, 3727, 3726 CG2275, CG2275, CG2275 B Azor CYP3A4, CYP3A43 1576, 64816 CG9438, CG9438 O Azur A MAPT 4137 CG31057 B Azure B MAPT 4137 CG31057 B BA (VAN) CYP3A4, CYP3A7 1576, 1551 CG9438, CG9438 O Baclofen HTR1A 3350 CG7485 O Bagren CYP3A4 1576 CG9438 O baicalein IGF1R, CCNB1, CDK4, 3480, 891, 1019, 983, CG1842, CG3510, CG5072, O CDC2, PLAT 5327 CG5363, CG13744 Barnidipine ABCB1 5243 CG3879 O BAY 11-7085 CCND1, GORASP1 595, 64689 CG9096, CG7809 B Beflavin CYP4F3, SF4 4051, 57794 CG3466, CG31550 B Benidipine ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O benzoyl- KDR 3791 CG8222 O staurosporine beraprost PLAT 5327 CG13744 O Berbamine HSP90AA1 3320 CG1242 O berberine ABCB1, JUNB, BEST1, 5243, 3726, 7439, 3727, CG3879, CG2275, CG6264, O JUND, JUN, CYP3A4 3725, 1576 CG2275, CG2275, CG9438 bergamottin CYP3A4 1576 CG9438 O bergaptol CYP3A4 1576 CG9438 O BESTATIN CCND1 595 CG9096 B beta- ABCB1 5243 CG3879 O citronellol beta-eudesmol FGF2 2247 CG4608 B beta- OPRM1 4988 CG7285 B funaltrexamine beta-gamma- RAC1 5879 CG2248 B iminotriphosphate bexarotene PSMD12, CCND3, CCND1 5718, 896, 595 CG1100, CG9096, CG9096 B Bezafibrate ABCB4, CYP3A4 5244, 1576 CG3879, CG9438 O BI D1870 RPS6KA3, RPS6KA6, RPS6KA1, 6197, 27330, 6195, 6196 CG17596, CG17596, CG17596, O RPS6KA2 CG17596 biapigenin CYP3A4 1576 CG9438 O BIBF 1000 FGF2 2247 CG4608 B BIBW 22 ABCB1 5243 CG3879 O bifeprunox HTR1A 3350 CG7485 O Bisoprolol CYP3A4 1576 CG9438 O Bisphenol A- CLTB 1212 CG6948 B Glycidyl Methacrylate bizelesin SERPINB3 6317 CG9456 B Bleomycin FGF7, TSC1, ABCB1, HSPA1A 2252, 7248, 5243, 3303 CG4608, CG6147, CG3879, O CG5436 BM 41.440 PCSK7 9159 CG10772 O BMS 310705 CYP3A4 1576 CG9438 O BMS-262084 ABCB1 5243 CG3879 O BMS453 CDK2 1017 CG5363 B BMS-470539 TUBB3 10381 CG3401 B BMY 7378 HTR1A 3350 CG7485 O Borrelia- PLG 5340 CG13744 O burgdorferi bortezomib CYP27A1, JUND, JUN, 1593, 3727, 3725, 10376, CG6042, CG2275, CG2275, B TUBA1B, HSPA1A, JUNB, 3303, 3726, 5696, CG1913, CG5436, PSMB8, PSMB5, ABCB1, 5693, 5243, 595, 1965, CG2275, CG12323, CG12323, CCND1, EIF2S1, MAGT1, 84061, 9531, 3308, CG3879, CG9096, BAG3, HSPA4, HSPA5, 3309, 3315, 3316, CG9946, CG7830, HSPB1, HSPB2, 3320, 64689 CG32130, CG6603, CG5436, HSP90AA1, GORASP1 CG14207, CG14207, CG1242, CG7809 bosentan CYP3A4 1576 CG9438 O bosutinib CDK2 1017 CG5363 B Bo-Xan ABCB1, IK 5243, 3550 CG3879, CG18005 B Brefeldin A JUN, CCNB1, JUND, HSPA5, 3725, 891, 3727, 3309, CG2275, CG3510, CG2275, O JUNB, YIF1A 3726, 10897 CG5436, CG2275, CG5484 bremazocine OPRK1, OPRM1 4986, 4988 CG7285, CG7285 B bryostatin JUNB, ABCB1, JUN, JUND 3726, 5243, 3725, 3727 CG2275, CG3879, CG2275, B CG2275 Budesonide CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O bufalin CYP24A1, MYB 1591, 4602 CG6042, CG9045 B Bumetanide BEST1 7439 CG6264 B Bupivacaine LPA 4018 CG13744 O Buprenorphine CYP3A4, OPRM1, OPRK1 1576, 4988, 4986 CG9438, CG7285, CG7285 B Buspirone HTR1A, CYP3A4 3350, 1576 CG7485, CG9438 O Buthionine ABCB1 5243 CG3879 O Buthionine SERPINB6 5269 CG9456 B Sulfoximine cabergoline KDR 3791 CG8222 O CACP PCBD1, PCSK5, PPP1R15A, 5092, 5125, 23645, 10467, CG1963, CG10772, CG3825, B ZNHIT1, JUNB, JUN, 3726, 3725, 57626, CG31917, CG2275, KLHL1, HSPA5, PDXP, 3309, 57026, 3728, CG2275, CG17754, JUP, GORASP1, RPSA, 64689, 3921, 6317, CG5436, CG4755, CG11579, SERPINB3, EIF4G1, 1981, 6591, 5269, CG7809, CG14792, SNAI2, SERPINB6, 1958, 1965, 2321, 7430, CG9456, CG10811, EGR1, EIF2S1, FLT1, 3727, 595, 3082, CG3758, CG9456, CG7847, EZR, JUND, CCND1, HGF, 1676, 3148, 1434, 3315, CG9946, CG8222, DFFA, HMGB2, CSE1L, 3480, 3316, 3303, CG10701, CG2275, HSPB1, IGF1R, HSPB2, 3320, 3717 CG9096, CG13744, CG8357, HSPA1A, HSP90AA1, CG17921, CG13281, JAK2 CG14207, CG1842, CG14207, CG5436, CG1242, CG1594 Calcijex CYP24A1, PSMD12, KSR1, 1591, 5718, 8844, 1594 CG6042, CG1100, CG2899, B CYP27B1 CG6042 Calcimycin EGR1, JUN, CPA1, HSP90B1, 1958, 3725, 1357, 7184, CG7847, CG2275, CG14820, B HSPA5, HSPA4, 3309, 3308, 8655 CG1242, CG5436, DYNLL1 CG6603, CG5450 calphostin C KDR, FGF13, FGF2, JUND, 3791, 2258, 2247, 3727, CG8222, CG4608, CG4608, B ADAMTS1, JUNB, JUN 9510, 3726, 3725 CG2275, CG14869, CG2275, CG2275 Calyculin EGR1, GSK3B, ETV5, MAPT, 1958, 2932, 2119, 4137, CG7847, CG2621, CG6892, 0 PPA1 5464 CG31057, CG4634 Camptothecin GSK3B, MYB, CCNA2, RPSA, 2932, 4602, 890, 3921, CG2621, CG9045, CG3510, 0 HGF, MAPT, ABCB1 3082, 4137, 5243 CG14792, CG13744, CG31057, CG3879 candesartan BEST1 7439 CG6264 B candoxatril MME 4311 CG9565 O candoxatrilat MME 4311 CG9565 O Canef CPB2, CYP3A4, LPA, PPA1, 1361, 1576, 4018, 5464, CG14820, CG9438, CG13744, O HGF 3082 CG4634, CG13744 CAPE CCND1, ABCB1 595, 5243 CG9096, CG3879 O capsanthin ABCB1 5243 CG3879 O capsazepine PCSK7 9159 CG10772 O Carbamazepine JUND, JUNB, CYP4F3, 3727, 3726, 4051, 1576, CG2275, CG2275, CG3466, B CYP3A4, ABCB1, JUN 5243, 3725 CG9438, CG3879, CG2275 carbamic acid FAAH, ABCB1 2166, 5243 CG6007, CG3879 O Cardiolipins RPS6KA3, FOXD3 6197, 27022 CG17596, CG3668 B Cardioplegic PIK3C2A 5286 CG11621 O Solutions carebastine ABCB1 5243 CG3879 O carfentanil OPRM1 4988 CG7285 B Carisoprodol DDX3X 1654 CG9748 O CARNOSOL CCNB1 891 CG3510 B carvacrol JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 B carvedilol ABCB1 5243 CG3879 O Casodex CYP4F3, TMSB4X, EZR 4051, 7114, 7430 CG3466, CG4944, CG10701 B caspofungin CYP3A4 1576 CG9438 O casticin CDC2, CCNA2 983, 890 CG5363, CG3510 B catechins HGF, IK, POLS 3082, 3550, 11044 CG13744, CG18005, CG11265 B CD 437 JUNB, HSPA5, PPP1R15A, 3726, 3309, 23645, 64689, CG2275, CG5436, CG3825, B GORASP1, JUN, JUND, 3725, 3727, 10628 CG7809, CG2275, TXNIP CG2275, CG18745 Cefotaxime CYP27A1 1593 CG6042 B Ceftazidime CYP27A1 1593 CG6042 B celecoxib ABCB1, PDPK1, CDK2, 5243, 5170, 1017, 3309, CG3879, CG1210, CG5363, O HSPA5, CCND1, GORASP1, 595, 64689, 1019 CG5436, CG9096, CDK4 CG7809, CG5072 Celiprolol ABCB1 5243 CG3879 O CEP 701 CYP3A4, (JAK2) 1576, (3717) CG9438, (CG1594) O cephalomannine CYP3A4 1576 CG9438 O cerivastatin CYP3A4, CDK2, CSE1L 1576, 1017, 1434 CG9438, CG5363, CG13281 O Cerulenin RPSA 3921 CG14792 O Cetirizine ABCB1 5243 CG3879 O Cetirizine TSC1 7248 CG6147 O cetuximab KDR 3791 CG8222 O CGS 26303 ECE1 1889 CG9565 O CGS 35066 ECE1 1889 CG9565 O CGS 35601 MME 4311 CG9565 O Chloramphenicol CLTB 1212 CG6948 B chloroprocaine PHC2 1912 CG18414 O Chlorzoxazone CYP4F3 4051 CG3466 B chymostatin CAPN2, CAPNS1, FGF2 824, 826, 2247 CG8107, CG8107, CG4608 B cicaprost CCNA2 890 CG3510 B ciglitazone GORASP1, CCND1, NUPR1 64689, 595, 26471 CG7809, CG9096, CG6770 B Ciguatoxins CYP27A1 1593 CG6042 B Cillora KLHL1 57626 CG17754 O cilostazol CYP3A4, LPA 1576, 4018 CG9438, CG13744 O Cimetidine ABCB1, CYP3A4, CYP3A7, 5243, 1576, 1551, 4051 CG3879, CG9438, CG9438, B CYP4F3 CG3466 CINK4 CCND1 595 CG9096 B Cipol N HSPB1, JUNB, PDGFB, 3315, 3726, 5155, 57626, CG14207, CG2275, CG7103, B KLHL1, NUP214, PLAT, 8021, 5327, 5464, CG17754, CG3820, PPA1, GORASP1, JUND, 64689, 3727, 5479, CG13744, CG4634, PPIB, SERPINC1, CCND2, 462, 894, 1576, 8655, CG7809, CG2275, CG2852, CYP3A4, DYNLL1, 27022, 10105, 1593, CG9456, CG9096, FOXD3, PPIF, CYP27A1, 5243, 3309, 3316, CG9438, CG5450, CG3668, ABCB1, HSPA5, HSPB2, 3725, 3082, 489, 5478, CG2852, CG6042, JUN, HGF, ATP2A3, 23462 CG3879, CG5436, PPIA, HEY1 CG14207, CG2275, CG13744, CG32451, CG2852, CG11194 Ciprofloxacin CYP27A1, NF2 1593, 4771 CG6042, CG14228 B Ciprol CIDEA 1149 CG1975 O Cisapride CYP3A4, HTR4 1576, 3360 CG9438, CG6919 O Citalopram CYP3A4 1576 CG9438 O Citox CYP3A4 1576 CG9438 O CJ-15161 OPRK1 4986 CG7285 B Cladribine TSC1 7248 CG6147 O clavosine B PPA1 5464 CG4634 O clavulone II CCND1 595 CG9096 B clobazam CYP3A4 1576 CG9438 O Clodronic BEST1 7439 CG6264 B Acid Clofazimine ABCB1 5243 CG3879 O Clofibric ABCB5, ABCB4, CYP3A4 340273, 5244, 1576 CG3879, CG3879, CG9438 O Acid Clomipramine CYP3A4 1576 CG9438 O Clonazepam CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 B Clonidine MAPT, TBXAS1 4137, 6916 CG31057, CG3466 B clonidine- FOXD3 27022 CG3668 B displacing substance clopidogrel ABCB1, CYP3A4, SERPINC1 5243, 1576, 462 CG3879, CG9438, CG9456 B clotiazepam CYP3A4 1576 CG9438 O Clozapine CCND1, PSMD12, AXIN1, 595, 5718, 8312, 2932, CG9096, CG1100, CG7926, O GSK3B, PPA1, HTR1A, 5464, 3350, 4051, CG2621, CG4634, CYP4F3, CYP3A4 1576 CG7485, CG3466, CG9438 CMDBS 25 FGF2, FGF13 2247, 2258 CG4608, CG4608 B Co 2-1970 P11 8909 CG2145 O Colchicine MAPT, MAF, ABCB1, CYP3A4, 4137, 4094, 5243, 1576, CG31057, CG10034, CG3879, O PPIF, WNK3 10105, 65267 CG9438, CG2852, CG7177 Cordanum ABCB1 5243 CG3879 O cornuside GORASP1 64689 CG7809 B costunolide KDR 3791 CG8222 O Cotinine ABCB1 5243 CG3879 O Cotrim CYP4F3 4051 CG3466 B coumarin CSE1L 1434 CG13281 O coumarin CSE1L, CYP3A4 1434, 1576 CG13281, CG9438 O coumarin CSE1L, CYP3A4, SERPINC1 1434, 1576, 462 CG13281, CG9438, CG9456 B coumermycins JAK1 3716 CG1594 B CP 31398 TSC1 7248 CG6147 O CRA 026440 NCOR2 9612 CG7951 B CREBtide RPS6KA3 6197 CG17596 O Crestor CYP3A4 1576 CG9438 O Crodacid PSMD12 5718 CG1100 O cryptotanshinone CYP3A4 1576 CG9438 O cryptoxanthin CCND1 595 CG9096 B Cyclandelate SERPINC1 462 CG9456 B cyclohexane- HTR1A 3350 CG7485 O carboxylic acid (2-(4- (2-bromo-5- methoxybenzyl)piperazin- 1-yl)ethyl)- (2- trifluoro- methoxy- phenyl)amide cyclopamine SHH, CDK2 6469, 1017 CG4637, CG5363 B cyclopiazonic CYP3A4, ATP2A2 1576, 488 CG9438, CG32451 B acid cycloprodigiosin JUNB, JUN, JUND 3726, 3725, 3727 CG2275, CG2275, CG2275 B cyclosporin G CYP4F3, ABCB1 4051, 5243 CG3466, CG3879 O cyclotheonamide A PLAT 5327 CG13744 O Cyproterone SERPINC1 462 CG9456 B Acetate Cystamine KDR, RAC1, IK 3791, 5879, 3550 CG8222, CG2248, CG18005 B cytarabine JUN 3725 CG2275 B D 21266 ABCB1 5243 CG3879 O DA 8159 MMEL1 79258 CG9565 O DABS CRKL 1399 CG1587 B Dacarbazine CYP4F3 4051 CG3466 B DADA MCRS1 10445 CG1135 B DADSO JUND, JUNB, JUN, CYP3A4 3727, 3726, 3725, 1576 CG2275, CG2275, CG2275, O CG9438 daidzein JUNB, JUN, JUND, METAP2, 3726, 3725, 3727, 10988, CG2275, CG2275, CG2275, B MAP2 4133 CG4008, CG31057 Dalteparin HGF 3082 CG13744 O D-AM FOXD3 27022 CG3668 B danaproid SERPINC1 462 CG9456 B Danazol LPA 4018 CG13744 O Dapsone CYP4F3 4051 CG3466 B Daral CYP3A4, CYP24A1, TSC1, 1576, 1591, 7248, 3727, CG9438, CG6042, CG6147, B JUND, JUN, CYP27A1, 3725, 1593, 5154, CG2275, CG2275, PDGFA, CYP27B1, 1594, 3726 CG6042, CG7103, CG6042, JUNB CG2275 Darifenacin CYP4F3 4051 CG3466 B dasatinib CRKL, src, CYP3A4, NUP214, 1399, 6714, 1576, 8021, CG1587, CG7524, CG9438, O ABCB1 5243 CG3820, CG3879 DAU 6285 HTR4 3360 CG6919 O Daunorubicin ABCB1 5243 CG3879 O dauricine ABCB1 5243 CG3879 O Dayfen SER- 6318, 57472, 5269 CG9456, CG31137, CG9456 B PINB4, CNOT6, SERPINB6 Dddd-PGD2 HSPA4, HSPA1A, HSPA5 3308, 3303, 3309 CG6603, CG5436, CG5436 O decursin CCND1 595 CG9096 B Deferoxamine JUNB, PLG, CDC2, CCND1, 3726, 5340, 983, 595, CG2275, CG13744, CG5363, B JUND, CCNA2, HGF, 3727, 890, 3082, 3725, CG9096, CG2275, JUN, CDK2 1017 CG3510, CG13744, CG2275, CG5363 DEHP ABCB1 5243 CG3879 O dehydroaripiprazole CYP3A4 1576 CG9438 O Dehydroepiandrosterone GATA6 2627 CG3978 B Sulfate dehydroxy- ABCB1, GORASP1, CCND1 5243, 64689, 595 CG3879, CG7809, CG9096 B methylepoxy- quinomicin Delavirdine KLHL1, CYP3A4 57626, 1576 CG17754, CG9438 O delphinidin JUN, KDR 3725, 3791 CG2275, CG8222 O delta-1- PPA1 5464 CG4634 O pyrroline-5- carboxylate delta8-THC RPS6KA2, JUND, CDC2, 6196, 3727, 983, 6197, CG17596, CG2275, CG5363, O RPS6KA3, RPS6KA1 6195 CG17596, CG17596 Denagard CYP3A4 1576 CG9438 O denbinobin CRKL, GORASP1 1399, 64689 CG1587, CG7809 B denosumab BEST1 7439 CG6264 B deoxyhypusine EIF5 1983 CG9177 B deoxyverrucosidin HSPA5 3309 CG5436 O Depas CYP3A4, CSE1L 1576, 1434 CG9438, CG13281 O dephosphono- PPA1 5464 CG4634 O calyculin A Deproceptin OPRM1 4988 CG7285 B deramciclane CYP3A4 1576 CG9438 O dermorphin OPRM1 4988 CG7285 B desethyl- CYP3A4 1576 CG9438 O chloroquine desloratadine ABCB1 5243 CG3879 O desmethylazelastine CYP3A4 1576 CG9438 O Desmethyldeprenyl CYP3A4 1576 CG9438 O desmethyl- CYP3A4 1576 CG9438 O tamoxifen DEVD-CHO MST1 4485 CG13744 O dexecadotril MME 4311 CG9565 O dexloxiglumide CYP4F3 4051 CG3466 B Dextropropoxyphene CYP3A4 1576 CG9438 O Diaben CYP3A4 1576 CG9438 O Diacomit CYP3A4 1576 CG9438 O diadenosine CDC2 983 CG5363 B tetraphosphate Didanosine BEST1 7439 CG6264 B dillapiol CYP3A4 1576 CG9438 O Diltiazem PREP, CYP3A4, ABCB1, 5550, 1576, 5243, 4051 CG5355, CG9438, CG3879, B CYP4F3 CG3466 Dinoprostone PSMD12, RAC1, TSC1, 5718, 5879, 7248, 3727, CG1100, CG2248, CG6147, O JUND, FGF9, JUN, PHC2, 2254, 3725, 1912, CG2275, CG4608, JAK3, FGF2, VEGFC, 3718, 2247, 7424, 6936, CG2275, CG18414, CG1594, C2orf3, FGF7, HGF, 2252, 3082, 1386, CG4608, CG7103, ATF2, MAP4K1, ABCB1, 11184, 5243, 595, CG1965, CG4608, CCND1, JUNB, EGR1, 3726, 1958, 182 CG13744, CG30420, CG7097, JAG1 CG3879, CG9096, CG2275, CG7847, CG6127 Diosgenin GORASP1 64689 CG7809 B diosmetin RAC1 5879 CG2248 B dioxirane TBXAS1 6916 CG3466 B Dioxolan RAC1 5879 CG2248 B Dipyrone CYP4F3, CYP3A4 4051, 1576 CG3466, CG9438 O Disopyramide MAF, PPA1, PREP 4094, 5464, 5550 CG10034, CG4634, CG5355 O Ditiocarb HSPA1B, HSPA2 3304, 3306 CG31449, CG5436 O Dizocilpine TSC1, HTR1A, CCND1 7248, 3350, 595 CG6147, CG7485, CG9096, B Maleate DNSC1 CYP3A4, SERPINC1 1576, 462 CG9438, CG9456 B Doca EGR1 1958 CG7847 O dofequidar ABCB1 5243 CG3879 O Dolomin CSE1L 1434 CG13281 O Domperidone ABCB1 5243 CG3879 O Doxazosin HTR1A 3350 CG7485 O doxifluridine STUB1 10273 CG5203 B Doxycycline NOTCH1, MYB, JUN, CYP3A4, 4851, 4602, 3725, 1576, CG3936, CG9045, CG2275, B FGF7 2252 CG9438, CG4608 DPC 681 CYP3A4 1576 CG9438 O DPCPX CPA1 1357 CG14820 B DPPH JAG1 182 CG6127 O Droxia JUN, ABCB1, CYP3A4, 3725, 5243, 1576, 27022, CG2275, CG3879, CG9438, B FOXD3, CDC2 983 CG3668, CG5363 Drysol MAPT 4137 CG31057 B duloxetine MAPT 4137 CG31057 B Durapatite JAK1, PPA1 3716, 5464 CG1594, CG4634 O Dursbanoxon CYP3A4 1576 CG9438 O DX 9065a HGF 3082 CG13744 O Dxms PLAT, RPSA, SLC5A5, 5327, 3921, 6528, 3726, CG13744, CG14792, CG32669, B JUNB, JUND, FGF2, MBL2, 3727, 2247, 4153, CG2275, CG2275, MME, TSC1, CYP4Z1, 4311, 7248, 199974, CG4608, CG7763, HSPB2, HSPB8, FGF7, 3316, 26353, 2252, CG9565, CG6147, CG3466, VEGFC, CCND1, CHAT, 7424, 595, 1103, 5243, CG14207, CG14207, ABCB1, CYP4A11, CYP3A4, 1579, 1576, 84061, CG4608, CG7103, MAGT1, TXNIP, 10628, 896, 891, 1593, CG9096, CG12345, CG3879, CCND3, CCNB1, CYP27A1, 5708, 8313, 3082, CG3466, CG9438, PSMD2, AXIN2, HGF, 3320, 3725, 126393, CG7830, CG18745, HSP90AA1, JUN, HSPB6, 64689 CG9096, CG3510, CG6042, GORASP1 CG7762, CG7926, CG13744, CG1242, CG2275, CG4183, CG7809 dynapen ABCB1 5243 CG3879 O Dynatra RASA3, SSTR4, MAPT, 22821, 6754, 4137, 1992, CG6721, CG7285, CG31057, B SER- 6916, 27022, 10988, CG9456, CG3466, PINB1, TBXAS1, FOXD3, 84062, 1357, 3350, CG3668, CG4008, CG6856, METAP2, DTN1, CPA1, 3308, 4133, 5464, CG14820, CG7485, HTR1A, HSPA4, MAP2, 6751, 4988, 4771 CG6603, CG31057, PPA1, SSTR1, OPRM1, CG4634, CG7285, CG7285, NF2 CG14228 dynorphin OPRK1 4986 CG7285 B dysidenin OPRK1 4986 CG7285 B dysprosium SLC5A5 6528 CG32669 O dystrobrevin MAPT 4137 CG31057 B E 10 MAF, CCND1 4094, 595 CG10034, CG9096 B EACA PLG, SERPINC1 5340, 462 CG13744, CG9456 O ebastine SERPINC1 462 CG9456 B ebrotidine CYP4F3 4051 CG3466 B Econ PDPK1, CYP4F2, FYN, 5170, 8529, 2534, 3550, CG1210, CG3466, CG7524, B IK, PCSK7 9159 CG18005, CG10772 econazole PCSK7 9159 CG10772 O ecteinascidin CYP3A4, ABCB1, CYP4F3 1576, 5243, 4051 CG9438, CG3879, CG3466 O 743 ectoine CYP4F3 4051 CG3466 B Edex MME, ATP1B1, PDGFB, 4311, 481, 5155, 1260, CG9565, CG9258, CG7103, O CNGA2, PLAT 5327 CG7779, CG13744 Edrophonium PLAT 5327 CG13744 O efavirenz ABCB1, MAPT, KLHL1, 5243, 4137, 57626, 4051, CG3879, CG31057, CG17754, B CYP4F3, CYP3A4 1576 CG3466, CG9438 efrapeptin CYP3A4 1576 CG9438 O EGCg FGF1, HSPA5, IGF1R, 2246, 3309, 3480, 1017, CG4608, CG5436, CG1842, B CDK2, RPSA, JUND, FGF2, 3921, 3727, 2247, CG5363, CG14792, ABCB1, HSPA4, JUN, 5243, 3308, 3725, 3726, CG2275, CG4608, CG3879, JUNB, HGF 3082 CG6603, CG2275, CG2275, CG13744 EGRck HGF 3082 CG13744 O EHT 1864 PLAT 5327 CG13744 O eletriptan RAC1 5879 CG2248 B Embelin CYP3A4 1576 CG9438 O embellistatin GORASP1 64689 CG7809 B EMD 53998 FGF2 2247 CG4608 B EMD 61753 TNC 3371 CG5550 O emetine OPRK1 4986 CG7285 B E-MIX 80 CCND1 595 CG9096 B Emodin CCND1, JUND, RAC1, KDR, 595, 3727, 5879, 3791, CG9096, CG2275, CG2248, B GORASP1, JUN, JUNB 64689, 3725, 3726 CG8222, CG7809, CG2275, CG2275 Empecid CYP3A4, CYP3A7, THOC4 1576, 1551, 10189 CG9438, CG9438, CG1101 O emtricitabine THOC4 10189 CG1101 B enadoline KLHL1 57626 CG17754 O Enalapril KLHL1, PLAT 57626, 5327 CG17754, CG13744 O Enalaprilat PLAT 5327 CG13744 O Enediynes PLAT 5327 CG13744 O Enelone CCNA2 890 CG3510 B Enoximone ATF2 1386 CG30420 B EPIB MME 4311 CG9565 O Epicar CYP4A11 1579 CG3466 B epicatechin SERPINB3 6317 CG9456 B gallate epimedin C CCND1 595 CG9096 B Epoprostenol SER- 462, 5879, 1576, 2277, CG9456, CG2248, CG9438, O PINC1, RAC1, CYP3A4, 2246 CG7103, CG4608 FIGF, FGF1 Epostane FGF1 2246 CG4608 B Epothilones FOXD3 27022 CG3668 B epoxybergamottin ABCB1 5243 CG3879 O epsilon- CYP3A4 1576 CG9438 O viniferin eptifibatide CYP4F3 4051 CG3466 B ergotamine PLAT 5327 CG13744 O eriocalyxin B HTR1A 3350 CG7485 O erlotinib CCND1, ABCB1, JAK2, 595, 5243, 3717, 1576 CG9096, CG3879, CG1594, B CYP3A4 CG9438 erucin CYP3A4 1576 CG9438 O Eryc JUN, CYP3A4, ABCB1, 3725, 1576, 5243, 3082, CG2275, CG9438, CG3879, O HGF, JUND, PPA1, JUNB 3727, 5464, 3726 CG13744, CG2275, CG4634, CG2275 Eskazine EGR1, MAPT 1958, 4137 CG7847, CG31057 O Estramustine MAPT 4137 CG31057 B ET18-Ome MAPT 4137 CG31057 B Etfc cpd PCSK7 9159 CG10772 O Ethacrynic CYP3A4 1576 CG9438 O Acid Ethambutol GORASP1 64689 CG7809 B Etidronic ABCB1 5243 CG3879 O Acid Etodolac SER- 6317, 891, 1019, 2247, CG9456, CG3510, CG5072, B PINB3, CCNB1, CDK4, 890, 983, 1017 CG4608, CG3510, FGF2, CCNA2, CDC2, CDK2 CG5363, CG5363 Etoposide TOP2A, JUND, ABCB1, 7153, 3727, 5243, 3726, CG10223, CG2275, CG3879, B JUNB, SF4, JUN 57794, 3725 CG2275, CG31550, CG2275 etoricoxib JUN 3725 CG2275 B Etorphine CYP3A4 1576 CG9438 O etravirine OPRM1 4988 CG7285 B Eufor CYP4F3, CYP3A4, HTR1A 4051, 1576, 3350 CG3466, CG9438, CG7485 O eumelanin HTR1A 3350 CG7485 O eupatilin CCND1, CCNB1, CDK2 595, 891, 1017 CG9096, CG3510, CG5363 B everolimus CDK2 1017 CG5363 B Evex CCNB1, NOTCH1, TSC1, 891, 4851, 7248, 9611, CG3510, CG3936, CG6147, O NCOR1, NCOR2, QRSL1, 9612, 55278, 3727, CG7951, CG7951, JUND, PLAT, PLG, JUNB, 5327, 5340, 3726, 3309, CG6007, CG2275, CG13744, HSPA5, JAG1, JUN, 182, 3725, 4292, CG13744, CG2275, MLH1, TBXAS1, KDR, 6916, 3791, 4137, 1958, CG5436, CG6127, MAPT, EGR1, YES1, IGF1R, 7525, 3480, 1594, CG2275, CG11482, CG3466, CYP27B1, EGR3, 1960, 6752, 7430, CG8222, CG31057, SSTR2, EZR, SERPINC1, 462, 6469, 6591, 3921, CG7847, CG7524, SHH, SNAI2, RPSA, 6434, 6751, 1576, CG1842, CG6042, CG7847, SFRS10, SSTR1, CYP3A4, 7439, 2932, 4899, 4051, CG7285, CG10701, BEST1, GSK3B, NRF1, 10521, 7114, 5243, CG9456, CG4637, CYP4F3, DDX17, 4478, 2200, 9352, CG3758, CG14792, CG10128, TMSB4X, ABCB1, MSN, 2258, 1017, 983, 6597, CG7285, CG9438, FBN1, TXNL1, FGF13, 595, 1357, 1593, 901, CG6264, CG2621, CDK2, CDC2, SMARCA4, 2626, 3146, 3303, CG3114, CG3466, CG10279, CCND1, CPA1, CYP27A1, 2254, 3082, 3316, 26353, CG4944, CG3879, CCNG2, GATA4, HMGB1, 25800, 1019, 2249, CG10701, CG3936, HSPA1A, FGF9, HGF, 2252, 890, 2247, CG5495, CG4608, CG5363, HSPB2, HSPB8, SLC39A6, 27022, 5045, 3315 CG5363, CG5942, CDK4, FGF4, FGF7, CG9096, CG14820, CG6042, CCNA2, FGF2, FOXD3, CG11525, CG3992, FURIN, HSPB1 CG17921, CG5436, CG4608, CG13744, CG14207, CG14207, CG6817, CG5072, CG4608, CG4608, CG3510, CG4608, CG3668, CG10772, CG14207 Evodin HSPB1 3315 CG14207 B exenatide CCND1, TXNIP, JAK1, 595, 10628, 3716, 1958 CG9096, CG18745, CG1594, B EGR1 CG7847 Extina CYP4F3, KSR1, ABCB1, 4051, 8844, 5243, 896, CG3466, CG2899, CG3879, O CCND3, CYP3A4, CYP4F2 1576, 8529 CG9096, CG9438, CG3466 ezetimibe CYP4F2 8529 CG3466 B F 11440 ABCB1 5243 CG3879 O Fanchinine GORASP1, ABCB1, CCND1, 64689, 5243, 595, 2247 CG7809, CG3879, CG9096, B FGF2 CG4608 F-Ara-A HTR1A 3350 CG7485 O febuxostat CYP3A5, CYP4F3, 1577, 4051, (2247) CG3466, CG3466, (CG4608) B (FGF2) felbamate CYP4F3 4051 CG3466 B Felodipine ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O fenitrothion CYP3A4 1576 CG9438 O fenofibric CYP3A4, CYP4A11 1576, 1579 CG9438, CG3466 O acid Fenoprofen SLC5A8, (CYP4A11) 160728, (1579) CG8451, (CG3466) B Fenretinide TUBB3, SF4, JAK1, EIF2S1, 10381, 57794, 3716, CG3401, CG31550, CG1594, O JUN, PLAT, CCND1 1965, 3725, 5327, 595 CG9946, CG2275, CG13744, CG9096 fexofenadine CCND1 595 CG9096 B fingolimod ABCB1 5243 CG3879 O fipronil JAK3 3718 CG1594 B fisetin CDK6, CDK4, GORASP1 1021, 1019, 64689 CG5072, CG5702, CG7809 O FLCZ CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Flecainide ABCB1 5243 CG3879 O Flesinoxan PREP 5550 CG5355 O flibanserin HTR1A 3350 CG7485 O Floxacillin CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Fludeoxyglucose ABCB1 5243 CG3879 O F 18 Flunarizine JAG1 182 CG6127 O fluorexon ABCB1 5243 CG3879 O Fluorouracil PCSK7, MLH1, TXNIP, 9159, 4292, 10628, 7439, CG10772, CG11482, CG18745, O BEST1, WNK1, TBXAS1, 65125, 6916, 890, CG6264, CG7177, CCNA2, CPA1, ABCB1, 1357, 5243, 1958, CG3466, CG3510, EGR1, FGF7, HSPA4, 2252, 3308, 1434, 64689 CG14820, CG3879, CG7847, CSE1L, GORASP1 CG4608, CG6603, CG13281, CG7809 Fluparoxan GORASP1 64689 CG7809 B Flupenthixol HTR1A 3350 CG7485 O fluvoxamine ABCB1, CYP3A4, HTR1A 5243, 1576, 3350 CG3879, CG9438, CG7485 O fondaparinux HTR1A 3350 CG7485 O Fonofos SERPINC1 462 CG9456 B Format CYP3A4 1576 CG9438 O Forskolin TUBB3, PLAT, PAX6, FGF7, 10381, 5327, 5080, 2252, CG3401, CG13744, CG11186, O CYP27B1, SLC5A5, 1594, 6528, 9128, CG4608, CG6042, PRPF4, ATP1B1, OPRL1, 481, 4987, 4478, 3146, CG32669, CG6322, MSN, HMGB1, PDGFB, 5155, 4137, 6751, CG9258, CG7285, CG10701, MAPT, SSTR1, JUN, 3725, 491, 4988, 5243, CG17921, CG7103, ATP2B2, OPRM1, ABCB1, 595, 1103, 2627, CG31057, CG7285, CCND1, CHAT, GATA6, 170690, 1958, 2247, CG2275, CG2198, CG7285, ADAMTS16, EGR1, 2324, 1576, 3350, 3082 CG3879, CG9096, FGF2, FLT4, CYP3A4, CG12345, CG3978, HTR1A, HGF CG14869, CG7847, CG4608, CG8222, CG9438, CG7485, CG13744 fosamprenavir HGF 3082 CG13744 O Foscarnet CYP3A4 1576 CG9438 O Frakefamide PPA1 5464 CG4634 O fucoidan KDR, FGF2, HGF, SERPINC1, 3791, 2247, 3082, 462, CG8222, CG4608, CG13744, B PLG 5340 CG9456, CG13744 fulvestrant JUN, CCND2, ATF2, CCND1 3725, 894, 1386, 595 CG2275, CG9096, CG30420, B CG9096 Fura-2 ABCB1, PCSK7 5243, 9159 CG3879, CG10772 O furafylline CYP3A4, FURIN 1576, 5045 CG9438, CG10772 O Furylfuramide FURIN 5045 CG10772 O FYDE PREP, X1, FOXD3, GORASP1, 5550, 7494, 27022, 64689, CG5355, CG9415, CG3668, B JUN, PDXP, MAPT 3725, 57026, 4137 CG7809, CG2275, CG4755, CG31057 Gambogic acid CDC2, KDR 983, 3791 CG5363, CG8222 B gedunin KDR 3791 CG8222 O gefitinib CYP3A4, (HSP90AA1) 1576, (3320) (CG1242), CG9438 O Geldanamycin HSPA4, HSPA2, HSPA1B, 3308, 3306, 3304, 3309, CG6603, CG5436, CG31449, B HSPA5, STUB1, HSPB1, 10273, 3315, 3725, CG5436, CG5203, JUN, RAC1, CCNB1, 5879, 891, 595, 904, CG14207, CG2275, CCND1, CCNT1, FGF2, 2247, 983, 1017, 3082, CG2248, CG3510, CG9096, CDC2, CDK2, HGF, HSP90AA1, 3320, 11140, 3303 CG6292, CG4608, CDC37, HSPA1A CG5363, CG5363, CG13744, CG1242, CG12019, CG5436 Gemfibrozil CYP3A4, PLG, JUNB, SLC22A7, 1576, 5340, 3726, 10864, CG9438, CG13744, CG2275, B JUN, JUND 3725, 3727 CG8654, CG2275, CG2275 genipin JUND 3727 CG2275 B Gentamicins JUN 3725 CG2275 B gepirone CYP3A4, HTR1A 1576, 3350 CG9438, CG7485 O Gestodene HTR1A 3350 CG7485 O GF 120918 CYP3A4, ABCB1, KLHL1 1576, 5243, 57626 CG9438, CG3879, CG17754 O GGTI 298 KLHL1 57626 CG17754 O GI 129471 CDK2 1017 CG5363 B Ginkgo- JUND, CYP3A4, CYP4F3, 3727, 1576, 4051, 3726, CG2275, CG9438, CG3466, O biloba- JUNB, JUN, PLAT, CYP27B1 3725, 5327, 1594 CG2275, CG2275, extract CG13744, CG6042 glabridin CYP27B1 1594 CG6042 B GLCa SERPINC1, EXT1 462, 2131 CG9456, CG10117 B Glumin THOC4, MSN, HSP90AA1, 10189, 4478, 3320, 3337, CG1101, CG10701, CG1242, B DNAJB1, HSPA8 3312 CG10578, CG31449 Glycyron JUND, KLHL1, HMGB1, 3727, 57626, 3146, 3726, CG2275, CG17754, CG17921, B JUNB, JUN, GORASP1 3725, 64689 CG2275, CG2275, CG7809 glyox GORASP1 64689 CG7809 B Gnidimacrin CYP27B1 1594 CG6042 B gossypetin CDK2 1017 CG5363 B gossypol AGL, CCND1, GORASP1 178, 595, 64689 CG9485, CG9096, CG7809 B GR 113808 GORASP1 64689 CG7809 B grifolin CCND1, CDK4 595, 1019 CG9096, CG5072 B Grofo CYP4F3, CYP3A4, ABCB1 4051, 1576, 5243 CG3466, CG9438, CG3879 O Guggulsterone ABCB1, CCND1 5243, 595 CG3879, CG9096 O gusperimus HSPA8, HSP90AA1 3312, 3320 CG31449, CG1242 B Harzol CCNB1, TUBA1B, MAP2, 891, 10376, 4133, 983 CG3510, CG1913, CG31057, B CDC2 CG5363 Hbim OPRL1, KDR 4987, 3791 CG7285, CG8222 B HESPERETIN KDR 3791 CG8222 O Hexadimethrine CDK4 1019 CG5072 O HMBA SERPINC1 462 CG9456 B hypsiziprenol FGF4 2249 CG4608 B A9 hypusine CCND1 595 CG9096 B hyrtioerectine A EIF5 1983 CG9177 B ibandronic EYA1 2138 CG9554 O acid IBMX JAK3, MME, HGF, LPA 3718, 4311, 3082, 4018 CG1594, CG9565, CG13744, O CG13744 I-BOP CCND1, EYA1 595, 2138 CG9096, CG9554 B Ibotenic Acid LPA 4018 CG13744 O Icosapent PLAT 5327 CG13744 O ICRF 193 POLS 11044 CG11265 B idebenone TOP2B 7155 CG10223 B IDN 5390 HSPA4 3308 CG6603 O Ifosfamide TUBB3 10381 CG3401 B Ifosfamide CYP4F3 4051 CG3466 B IGF-1 CYP3A4 1576 CG9438 O Iloprost RBM6, RAC1 10180, 5879 CG4887, CG2248 B imatinib CYP3A4, EGR1, JUN, CCND1, 1576, 1958, 3725, 595, CG9438, CG7847, CG2275, B PDGFB, CCND2, 5155, 894, 890, 3799, CG9096, CG7103, CCNA2, KIF5B, PCSK7, 9159, 3717, 3726, CG9096, CG3510, CG7765, JAK2, JUNB, KDR, HSPA4, 3791, 3308, 5243, 2247, CG10772, CG1594, ABCB1, FGF2, CDK2, 1017, 1399, 3082 CG2275, CG8222, CRKL, HGF CG6603, CG3879, CG4608, CG5363, CG1587, CG13744 imidafenacin ABCB1 5243 CG3879 O imperatorin CYP3A4 1576 CG9438 O Impulsin CCND1 595 CG9096 B Imrecoxib FAAH 2166 CG6007 B Imutex HIST2H3C, MAPT, HIST1H3C, 126961, 4137, 8352, CG5825, CG31057, CG5825, B BEST1, CYP3A7, 7439, 1551, 8353, 4051 CG6264, CG9438, HIST1H3E, CYP4F3 CG5825, CG3466 indazole CYP4F3 4051 CG3466 B Indinavir CYP4F3, CYP3A4, ABCB1 4051, 1576, 5243 CG3466, CG9438, CG3879 O indiplon ABCB1 5243 CG3879 O indirubin-3′- CYP3A4 1576 CG9438 O monoxime infliximab KDR, PSMD12 3791, 5718 CG8222, CG1100 O inogatran PSMD12 5718 CG1100 O Ipral CPB2 1361 CG14820 B Iprivask ABCB1 5243 CG3879 O ipsapirone PLG 5340 CG13744 O irbesartan JUNB, JUND, JUN, BEST1 3726, 3727, 3725, 7439 CG2275, CG2275, CG2275, B CG6264 Iressa RAC1, HGF, CCND1, CYP3A4, 5879, 3082, 595, 1576, CG2248, CG13744, CG9096, O IGF1R 3480 CG9438, CG1842 irinotecan PCSK7, CDC2, CYP3A4, 9159, 983, 1576, 57626, CG10772, CG5363, CG9438, O KLHL1, ABCB1 5243 CG17754, CG3879 irisolidone JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2275 B irofulven JUN 3725 CG2275 B Irox EIF5B 9669 CG10840 O Ismo PHC2 1912 CG18414 O Isobac CSE1L 1434 CG13281 O isochaihulactone CYP3A4 1576 CG9438 O Isodonol EGR1 1958 CG7847 O isoflavone IGF1R 3480 CG1842 O Isorhamnetin BEST1 7439 CG6264 B isosteviol ABCB1 5243 CG3879 O Isradipine POLS 11044 CG11265 B Istidina CYP3A4 1576 CG9438 O ITF 2357 ABCB1 5243 CG3879 O Itraconazole ABCB1, CYP3A4, CYP4F3 5243, 1576, 4051 CG3879, CG9438, CG3466 O Ivermectin KLHL1, ABCB1 57626, 5243 CG17754, CG3879 O ixabepilone ABCB1 5243 CG3879 O J 113397 CYP3A4 1576 CG9438 O J 113397 OPRL1 4987 CG7285 B jasplakinolide JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 B juglone JUND 3727 CG2275 B juzentaihoto MAPT 4137 CG31057 B K 252 CDC2, PPA1 983, 5464 CG5363, CG4634 B kaempferol CYP3A4, JAK3, FAAH, 1576, 3718, 2166, 3727, CG9438, CG1594, CG6007, B JUND, JUN, IK, JUNB 3725, 3550, 3726 CG2275, CG2275, CG18005, CG2275 KAFA JUNB 3726 CG2275 B kahweol CYP4F3 4051 CG3466 B Kainic Acid MAP2, METAP2, JUN 4133, 10988, 3725 CG31057, CG4008, CG2275 B kami-untan-to JUN 3725 CG2275 B Kaolin SERPINC1, PLG 462, 5340 CG9456, CG13744 B KB 2796 PLG 5340 CG13744 O K-DR PPA1 5464 CG4634 O Keloid ABCB1 5243 CG3879 O Kemi EGR1, PREP, NF2 1958, 5550, 4771 CG7847, CG5355, CG14228 O ketazocine NF2 4771 CG14228 B Keto- OPRK1 4986 CG7285 B pgf1alpha KKHA-761 SERPINC1 462 CG9456 B KN 62 HTR1A 3350 CG7485 O KN 93 NOTCH1, CDK4 4851, 1019 CG3936, CG5072 B KNK 437 HSPA1A, HSPB2, HSPB1, 3303, 3316, 3315, 3308 CG5436, CG14207, CG14207, B HSPA4 CG6603 KP372-1 HSPA4 3308 CG6603 O K-PAM CSE1L, HRB, SERPINC1 1434, 3267, 462 CG13281, CG3365, CG9456 B KPMK PDPK1 5170 CG1210 B KR 31831 GORASP1 64689 CG7809 B KRM 1648 KDR 3791 CG8222 O K-SR PPP2CA, GSK3B, GTF3C1 5515, 2932, 2975 CG7109, CG2621, CG7099 B kurarinone CYP3A4 1576 CG9438 O KYNA KDR 3791 CG8222 O L 685458 NOTCH1, HEY1 4851, 23462 CG3936, CG11194 B L797591 CYP3A4 1576 CG9438 O LAGA SSTR1 6751 CG7285 B Lamivudine CSE1L, KLHL1 1434, 57626 CG13281, CG17754 O lamotrigine KLHL1 57626 CG17754 O lanreotide HTR1A 3350 CG7485 O lapachenole PPA1 5464 CG4634 O lapatinib CYP3A4 1576 CG9438 O LAQ824 TUBA1B, HSP90AA1 10376, 3320 CG1913, CG1242 B laquinimod HSP90AA1 3320 CG1242 O latrunculin A TMSB4X, PCBD1 7114, 5092 CG4944, CG1963 O LBH589 TUBA1B, HSP90AA1 10376, 3320 CG1913, CG1242 B leflunomide PDPK1, FYN 5170, 2534 CG1210, CG7524 B lenalidomide JUND, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2275 B Lendorm JUN 3725 CG2275 B Lentinan CYP3A4 1576 CG9438 O Leukotriene JUNB, PLCB2, JUN, JUND 3726, 5330, 3725, 3727 CG2275, CG3620, CG2275, B B4 CG2275 Leukotriene JUN, ABCB5, KLHL1, JUND, 3725, 340273, 57626, CG2275, CG3879, CG17754, B C4 JUNB 3727, 3726 CG2275, CG2275 Leukotriene JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 B D4 leukotrienes HTR1A, SSTR4, SSTR1 3350, 6754, 6751 CG7485, CG7285, CG7285 B Levonorgestrel PLAT, PLG, JUN, CSE1L 5327, 5340, 3725, 1434 CG13744, CG13744, CG2275, B CG13281 liarozole CSE1L 1434 CG13281 O lintopride HTR4, (CYP3A4) 3360, (1576) CG6919, (CG9438) O liquiritin HTR4 3360 CG6919 O LMWH HSPB2, PLAT, MAPT, 3316, 5327, 4137, 3320, CG14207, CG13744, CG31057, B HSP90AA1, HSPB1, PPIB, 3315, 5479, 462, CG1242, CG14207, SERPINC1, JUN, JUNB, 3725, 3726, 3727, 3082, CG2852, CG9456, JUND, HGF, CDK2, 1017, 5340, 2931, CG2275, CG2275, CG2275, PLG, GSK3A, ADAMTS5, 11096, 2324, 2247, CG13744, CG5363, FLT4, FGF2, DDX5, RPSA, 1655, 3921, 595, 64689, CG13744, CG2621, CCND1, GORASP1, 2258, 2246, 2252, CG14869, CG8222, FGF13, FGF1, FGF7, 26281, 1361, 1593 CG4608, CG10279, CG14792, FGF20, CPB2, CYP27A1 CG9096, CG7809, CG4608, CG4608, CG4608, CG4608, CG14820, CG6042 LNAC HSPA5, CCND2, JUND, 3309, 894, 3727, 3082, CG5436, CG9096, CG2275, B HGF, ABCB1, JUN, PDPK1, 5243, 3725, 5170, CG13744, CG3879, HSPA4, HSPA1A, JUNB, 3308, 3303, 3726, 64689 CG2275, CG1210, CG6603, GORASP1 CG5436, CG2275, CG7809 lonafarnib GORASP1 64689 CG7809 B lonidamine ABCB1 5243 CG3879 O Loperamide CYP3A4, ABCB1, OPRM1 1576, 5243, 4988 CG9438, CG3879, CG7285 O lopinavir ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O Lopril PLAT, PLG 5327, 5340 CG13744, CG13744 O Loratadine ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O Lorazepam CYP3A4 1576 CG9438 O Lorex CPA1 1357 CG14820 B Losartan SLC22A12, CYP27B1, 116085, 1594, 4153, CG8654, CG6042, CG7763, B MBL2, CYP3A4 1576 CG9438 Lovan SMARCA4, PLG, SMARCA2 6597, 5340, 6595 CG5942, CG13744, CG5942 O loxiglumide SMARCA2 6595 CG5942 B L-T3 IK, CYP3A4 3550, 1576 CG18005, CG9438 B lupeol PPA1 5464 CG4634 O luteolin JUND, CYP3A4, IGF1R, 3727, 1576, 3480, 595, CG2275, CG9438, CG1842, B CCND1, HGF, JUN, JUNB 3082, 3725, 3726 CG9096, CG13744, CG2275, CG2275 lutetium JUNB 3726 CG2275 B Lutex SLC19A1, JUN, MAP2, 6573, 3725, 4133, 10988, CG14694, CG2275, CG31057, O METAP2, HSPB1, FAAH, 3315, 2166, 983, CG4008, CG14207, CDC2, PDGFB, PREP, 5155, 5550, 1017, 462, CG6007, CG5363, CDK2, SERPINC1, RPSA, 3921, 5243, 595, CG7103, CG5355, CG5363, ABCB1, CCND1, EIF4E1, 1978, 4137, 1576, 64689, CG9456, CG14792, MAPT, CYP3A4, GORASP1, 3082, 3316, 1959, CG3879, CG9096, HGF, HSPB2, 2252 CG8846, CG31057, CG9438, EGR2, FGF7 CG7809, CG13744, CG14207, CG7847, CG4608 LY 117018 FGF7 2252 CG4608 B LY 293111 CCNA2, CDK2 890, 1017 CG3510, CG5363 B LY 293284 CDK2 1017 CG5363 B LY 303511 HTR1A 3350 CG7485 O LY231514 EGR1 1958 CG7847 O mahanine TBXAS1 6916 CG3466 B Maleimides CCND1 595 CG9096 B Malix GSK3A 2931 CG2621 B manzamine A CYP3A4 1576 CG9438 O maraviroc GSK3A 2931 CG2621 B MBC1 CYP3A4 1576 CG9438 O MCYST-LR PPA1, PPP2CA 5464, 5515 CG4634, CG7109 O Mebumal PPP2CA 5515 CG7109 O Medemycin ATP2B2 491 CG2191 O Medroxyprogesterone CYP3A4, SERPINC1, MSN, 1576, 462, 4478, 3725 CG9438, CG9456, CG10701, B 17- JUN CG2275 Acetate Melatol CCND1, JUN, MAPT, CYP4F3, 595, 3725, 4137, 4051, CG9096, CG2275, CG31057, B FOXD3 27022 CG3466, CG3668 meletin JUNB, JUN, HSPB2, CCNB1, 3726, 3725, 3316, 891, CG2275, CG2275, CG14207, B GSK3B, TSC1, PLAT, 2932, 7248, 5327, CG3510, CG2621, ABCB1, CYP3A4, HSPB1, 5243, 1576, 3315, 983, CG6147, CG13744, CDC2, JUND, HSPA4, 3727, 3308, 3303, CG3879, CG9438, CG14207, HSPA1A, CDK2, HSP90AA1 1017, 3320 CG5363, CG2275, CG6603, CG5436, CG5363, CG1242 melitten PLAT, RAC1 5327, 5879 CG13744, CG2248 O meloxicam RAC1 5879 CG2248 B Memantine MAPT, CYP3A4 4137, 1576 CG31057, CG9438 B Menatetrenone CYP3A4 1576 CG9438 O MENT SERPINB3, SERPINB4 6317, 6318 CG9456, CG9456 B Mephenytoin SERPINB4 6318 CG9456 B Meprobamate CYP3A4 1576 CG9438 O MeSAdo JUN, MTAP, JUNB, JUND 3725, 4507, 3726, 3727 CG2275, CG4802, CG2275, B CG2275 mesalamine JUND 3727 CG2275 B Mesaton CPA1, JUN, CCNA2 1357, 3725, 890 CG14820, CG2275, CG3510 B mesoglycan CCNA2 890 CG3510 B Mesol FGF1 2246 CG4608 B metazachlor FOXD3 27022 CG3668 B Meth JUNB, MAPT, JUND, OPRM1, 3726, 4137, 3727, 4988, CG2275, CG31057, CG2275, O DTN1, JUN 84062, 3725 CG7285, CG6856, CG2275 methanopterin JUN 3725 CG2275 B Methorphan CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O Methoxsalen CYP4F3 4051 CG3466 B methoxymorphinan CYP3A4 1576 CG9438 O Methylprednisolone MBL2, SERPINC1 4153, 462 CG7763, CG9456 B Methylthio- SERPINC1 462 CG9456 B inosine Metkephamid PPA1 5464 CG4634 O Metopiron CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O Metribolone CDK4, GSK3B, FGF7 1019, 2932, 2252 CG5072, CG2621, CG4608 B Miazine FGF7 2252 CG4608 B miconazole CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O Mictonorm CYP4F3 4051 CG3466 B Midazolam CYP3A4, CYP4F3, ABCB1, 1576, 4051, 5243, 79258 CG9438, CG3466, CG3879, O MMEL1 CG9565 Mifepristone CYP3A4, NCOR1, CCNA2, 1576, 9611, 890, 1017, CG9438, CG7951, CG3510, B CDK2, ABCB1 5243 CG5363, CG3879 miglustat ABCB1 5243 CG3879 O milbemycin KDR 3791 CG8222 O Mimosine ABCB1 5243 CG3879 O mirtazapine EIF5 1983 CG9177 B Mit-C JUNB, PPP1R15A, FCN2, 3726, 23645, 2220, 4094, CG2275, CG3825, CG555, O MAF, JUN, SHH, JUND 3725, 6469, 3727 CG10034, CG2275, CG4637, CG2275 mithramycin A JUND 3727 CG2275 B Mitoxantrone ABCB1, KLHL1, JUN 5243, 57626, 3725 CG3879, CG17754, CG2275 O MK-0524 JUN 3725 CG2275 B MLN 944 TFDP1 7027 CG4654 B Molsidomine JUN 3725 CG2275 B Monensin HRB, HSPA4, CDK2, CCNA2, 3267, 3308, 1017, 890, CG3365, CG6603, CG5363, O CDC2, PLAT, CCND1, 983, 5327, 595, 1021, CG3510, CG5363, CDK6, CDK4 1019 CG13744, CG9096, CG5072, CG5072 monocillin I CYP3A4 1576 CG9438 O monodansylcadaverine HSP90AA1 3320 CG1242 O mono-N- CDK4 1019 CG5072 O demethyladinazolam Monorden HSP90AB1, HSPA4, FGF2, 3326, 3308, 2247, 3337, CG1242, CG6603, CG4608, B DNAJB1, HSP90AA1 3320 CG10578, CG1242 MORIN JUND, JUNB, ABCB1, JUN 3727, 3726, 5243, 3725 CG2275, CG2275, CG3879, O CG2275 morphine-3- JUN 3725 CG2275 B glucuronide mosapride HTR4, (CYP3A4) 3360, (1576) CG6919, (CG9438) O motapizone HTR4 3360 CG6919 O Motuporin MME 4311 CG9565 O moxifloxacin PPP2CA 5515 CG7109 O MRK 003 NOTCH4, NOTCH3 4855, 4854 CG3936, CG3936 B MTPA NOTCH3 4854 CG3936 B Muran PLG 5340 CG13744 O Muscarine FOXD3 27022 CG3668 B N-(4- CCND1 595 CG9096 B amino- phenethyl)spiroperidol N-(4- ABCB1 5243 CG3879 O amino- phenyl)maleimide N-(4-cyano- CYP3A7, CYP3A4 1551, 1576 CG9438, CG9438 O benzo (b) thiophene- 2- carbonyl)guanidine N-(8-amino-1- CYP3A4 1576 CG9438 O carboxyoctyl)- alanyl- proline N(alpha)-(4- HTR1A 3350 CG7485 O amino-4- deoxyp- teroyl)- N(delta)- hemiphthaloyl- L-ornithine N-(m-heptyl)- FGF1 2246 CG4608 B 5-chloro-1- naphthalene- sulfonamide N-3- HSP90AA1 3320 CG1242 O isoquinolinyl- 2-((4- pyridinyl- methyl)amino)benzamide NABU SLC19A1 6573 CG14694 O Naftalen GORASP1 64689 CG7809 B Naloxone CYP3A4 1576 CG9438 O Naltrexone OPRM1 4988 CG7285 B naltrindole OPRM1 4988 CG7285 B NAN-190 hydrobromide OPRK1 4986 CG7285 B nanchangmycin HTR1A 3350 CG7485 O Naphazoline NDUFAB1 4706 CG9160 O NARIGENIN CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O nateglinide ABCB1 5243 CG3879 O N- KDR 3791 CG8222 O benzyloxycarbonylprolyl- prolinal N- PREP 5550 CG5355 O dehydroxyzileuton N- CYP4F3 4051 CG3466 B desmethylclobazam nedaplatin CYP3A4 1576 CG9438 O Nefazodone CYP4F3, CYP3A4, HTR1A 4051, 1576, 3350 CG3466, CG9438, CG7485 O Nelfinavir CYP4F3, CSE1L, CYP3A4, 4051, 1434, 1576, 5243 CG3466, CG13281, CG9438, O ABCB1 CG3879 nemonapride ABCB1 5243 CG3879 O neodymium HTR1A 3350 CG7485 O Neomycin MAPT 4137 CG31057 B N- GTF3C1, HSPA4, EYA1 2975, 3308, 2138 CG7099, CG6603, CG9554 O ethylmaleimide netoglitazone SERPINB1 1992 CG9456 B neuromedin C TSC1 7248 CG6147 O Neut CCND1, ODC1 595, 4953 CG9096, CG8721 B Nevirapine CSE1L, ABCB1, KLHL1, 1434, 5243, 57626, 1576 CG13281, CG3879, CG17754, O CYP3A4 CG9438 Niacinamide TUBA1B, FGF6, MAPT, 10376, 2251, 4137, 1576 CG1913, CG4608, CG31057, B CYP3A4 CG9438 nicaraven CYP3A4 1576 CG9438 O Nicardipine CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Niceritrol ABCB1 5243 CG3879 O Nigericin LPA 4018 CG13744 O niguldipine EIF4G1 1981 CG10811 B Nimodipine ABCB1 5243 CG3879 O NK 104 RAC1, FGF2, PLAT 5879, 2247, 5327 CG2248, CG4608, CG13744 B NMDA FOXD3, MAP2, DMRT1, 27022, 4133, 1761, 3350, CG3668, CG31057, CG11094, O HTR1A, METAP2 10988 CG7485, CG4008 N- PLAT, CYP4F3 5327, 4051 CG13744, CG3466 O methylsulfonyl- 6-(2- propargyloxy- phenyl)hexanamide NN 703 METAP2 10988 CG4008 B Nobiletin ABCB1, JUN, JUND, CYP3A4, 5243, 3725, 3727, 1576, CG3879, CG2275, CG2275, O JUNB 3726 CG9438, CG2275 NOC 18 JUNB 3726 CG2275 B Nociceptin OPRL1, SSTR4, HTR1A, 4987, 6754, 3350, 6751, CG7285, CG7285, CG7485, B SSTR1, OPRM1 4988 CG7285, CG7285 noralfentanil OPRM1 4988 CG7285 B Norbinaltor- CYP3A4 1576 CG9438 O phiminenorcantharidin OPRK1 4986 CG7285 B Nordihydroguaiaretic JUN, IGF1R, JUND, JUNB 3725, 3480, 3727, 3726 CG2275, CG1842, CG2275, B Acid CG2275 Norethindrone PLAT, CYP3A4 5327, 1576 CG13744, CG9438 O noreximide CYP3A4 1576 CG9438 O norfluoxetine CYP4F3, CYP3A4 4051, 1576 CG3466, CG9438 B norlaudanosoline JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2275 B Nortilidine ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O norverapamil CYP3A4 1576 CG9438 O novobiocin HSP90AA1, PCSK5, CDC37 3320, 5125, 11140 CG1242, CG10772, CG12019 O NPI 031L TSC1, RAC1, IGF1R, MSN, 7248, 5879, 3480, 4478, CG6147, CG2248, CG1842, B MAPT, KCNK6, PDCD2, 4137, 9424, 5134, CG10701, CG31057, PCSK7, JUND, FAAH, 9159, 3727, 2166, 9611, CG1688, CG326, CG10772, NCOR1, HSP90AA1, 3320, 6317, 595, CG2275, CG6007, SER- 64689, 3726, 2247, CG7951, CG1242, PINB3, CCND1, GORASP1, 2252, 3082, 5243, 891, CG9456, CG9096, CG7809, JUNB, FGF2, FGF7, 3309, 983, 3718, 3725, CG2275, CG4608, HGF, ABCB1, CCNB1, 1591, 7439 CG4608, CG13744, HSPA5, CDC2, JAK3, JUN, CG3879, CG3510, CG5436, CYP24A1, BEST1 CG5363, CG1594, CG2275, CG6042, CG6264 NRDC BEST1 7439 CG6264 B NSC 23766 RAC1, NOTCH1 5879, 4851 CG2248, CG3936 B NSC 295558 NOTCH1 4851 CG3936 B NSC 366140 CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O NSC 663284 CYP4F3 4051 CG3466 B N-tert-butyl- CYP4F3 4051 CG3466 B 3-[4-(2- methoxy- phenyl)piperazin- 1-yl]-2- phenylpropanamide NU2058 CDC2 983 CG5363 B NU6102 CDK2 1017 CG5363 B nutlin 3 CDK4 1019 CG5072 O NVP-AEW541 ABCB1 5243 CG3879 O obovatol JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2275 B OC 144-093 JUN 3725 CG2275 B ochratoxin A KLHL1, FOXD3 57626, 27022 CG17754, CG3668 O Octreotide SSTR5, FGF2, SSTR1, 6755, 2247, 6751, 3480, CG7285, CG4608, CG7285, B IGF1R, FGF3, PPA1 2248, 5464 CG1842, CG4608, CG4634 Octreotide PPA1 5464 CG4634 O O- IGF1R 3480 CG1842 O demethyl- tramadol O- OPRM1 4988 CG7285 B desethylreboxetine oenothein B SSTR2 6752 CG7285 B Ogen FGF2, PLG 2247, 5340 CG4608, CG13744 B OH-pro PLG 5340 CG13744 O Oktan MBL2 4153 CG7763 B Olamine OPRM1 4988 CG7285 B olanzapine MEA1 4201 CG14341 O oleandrin JUN, JUND, JUNB 3725, 3727, 3726 CG2275, CG2275, CG2275 B oleylamide JUNB 3726 CG2275 B olmelin JUNB, JUN, JUND 3726, 3725, 3727 CG2275, CG2275, CG2275 B olomoucine MAPT, CDC2, CDK2, CDK4 4137, 983, 1017, 1019 CG31057, CG5363, CG5363, B CG5072 Olymp CDK4 1019 CG5072 O omalizumab PDXP 57026 CG4755 B omapatrilat CYP3A4 1576 CG9438 O omega-N- MME 4311 CG9565 O Methylarginine Omeprazole ABCB1, CYP3A4, CYP4F3 5243, 1576, 4051 CG3879, CG9438, CG3466 O omeprazole CYP4F3 4051 CG3466 B sulfone Ondansetron CPA1, CYP3A4, ABCB1 1357, 1576, 5243 CG14820, CG9438, CG3879 O ONO 1301 ABCB1 5243 CG3879 O Optef P11, PCBD1, VEGFC, PSMD6, 8909, 5092, 7424, 9861, CG2145, CG1963, CG7103, O HSPB8, TNC, CCND1, 26353, 3371, 595, CG5378, CG14207, ABCB1, CPA1, PIK3C2A, 5243, 1357, 5286, 3082, CG5550, CG9096, CG3879, HGF, SERPINC1, 462, 1576, 3350, CG14820, CG11621, CYP3A4, HTR1A, NUP214 8021 CG13744, CG9456, CG9438, CG7485, CG3820 Org 31540 NUP214 8021 CG3820 B Orphenadrine HGF 3082 CG13744 O OSI 930 CYP3A4 1576 CG9438 O OSU 03012 CCNA2, HSPA4 890, 3308 CG3510, CG6603 B Ouabain MAPT, ABCB1, JUN, ATP4B, 4137, 5243, 3725, 496, CG31057, CG3879, CG2275, B FGF13, FGF2 2258, 2247 CG9258, CG4608, CG4608 ovalicin FGF2 2247 CG4608 B Ovex CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O oxaliplatin NOTCH1, TXNL1, CDC2 4851, 9352, 983 CG3936, CG5495, CG5363 O oxatomide CDC2 983 CG5363 B oxcarbazepine CYP3A4 1576 CG9438 O Oxidopamine CCND1, JUN, GSK3B 595, 3725, 2932 CG9096, CG2275, CG2621 B oxymatrine GSK3B 2932 CG2621 B Oxytrol CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O Paclitaxel MAPT, JUND, CCND1, JUN, 4137, 3727, 595, 3725, CG31057, CG2275, CG9096, B TMSB4X, TUBA1B, 7114, 10376, 3315, CG2275, CG4944, HSPB1, PSMD2, EIF4E2, 5708, 1979, 1678, 1978, CG1913, CG14207, TIMM8A, EIF4E1, CCNB1, 891, 983, 8766, CG7762, CG8846, CG1728, CDC2, RAB11A, 5243, 2932, 2717, 64689, CG8846, CG3510, ABCB1, GSK3B, GLA, 3316, 1434, 3726, CG5363, CG5771, CG3879, GORASP1, HSPB2, CSE1L, 1576 CG2621, CG5731, JUNB, CYP3A4 CG7809, CG14207, CG13281, CG2275, CG9438 palytoxin CYP3A4 1576 CG9438 O pamidronate JUN 3725 CG2275 B p- CYP4F3 4051 CG3466 B Aminohippuric Acid panaxadiol BEST1 7439 CG6264 B pantoprazole CDK2 1017 CG5363 B PAPP CYP3A4 1576 CG9438 O Parthenolide GORASP1, ADAMTS4, HSPA1A 64689, 9507, 3303 CG7809, CG14869, CG5436 O Patulin HSPA1A 3303 CG5436 O pazopanib KDR, (EGR1) 3791, (1958) CG8222, (CG7847) PCSO KDR 3791 CG8222 O PD 169316 HSPB1, ATF2, HSPB2 3315, 1386, 3316 CG14207, CG30420, CG14207 B PD 173074 HSPB2 3316 CG14207 B PD 98059 PAX6, JUN, GORASP1, 5080, 3725, 64689, 3727, CG11186, CG2275, CG7809, B JUND, NPDC1, PHOX2A, 56654, 401, 3726, CG2275, CG30420, JUNB, PPA1, FGF2, CYP24A1, 5464, 2247, 1591, CG11182, CG2275, ADAMTS9, EGR1, 56999, 1958, 3082, 5340, CG4634, CG4608, CG6042, HGF, PLG, ABCB1, 5243, 595, 2258, CG14869, CG7847, CCND1, FGF13, CDK2, 1017, 2220 CG13744, CG13744, FCN2 CG3879, CG9096, CG4608, CG5363, CG555 PDBU ETV4, ABCB1 2118, 5243 CG6892, CG3879 O Pectenotoxin CDC2, EGR1 983, 1958 CG5363, CG7847 B II pegvisomant EGR1 1958 CG7847 O Pemetrexed SLC19A1, TBXAS1, MTAP 6573, 6916, 4507 CG14694, CG3466, CG4802 B pentosidine MTAP 4507 CG4802 B Pentoxifylline TSC1, CCNB1, FCN2 7248, 891, 2220 CG6147, CG3510, CG555 B Peplomycin GORASP1, PREP 64689, 5550 CG7809, CG5355 B Pepstatin A CYP3A4, PLG 1576, 5340 CG9438, CG13744 O Perazine PLG 5340 CG13744 O Perillol JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 B Perindopril JUND 3727 CG2275 B perylene MBL2 4153 CG7763 B bisimide phen MAPT 4137 CG31057 B phen PHC2 1912 CG18414 O phenanthrene MMEL1 79258 CG9565 O phenothiazines CYP4F3 4051 CG3466 B Phenprocoumon CSE1L, CYP3A4 1434, 1576 CG13281, CG9438 O Phenytoin CYP3A4, CYP4F3, KLHL1 1576, 4051, 57626 CG9438, CG3466, CG17754 B pheophorbide a KLHL1 57626 CG17754 O phloretin GSK3B, TXNIP 2932, 10628 CG2621, CG18745 B Picibanil TXNIP 10628 CG18745 B picric acid SMARCA2 6595 CG5942 B picropodo- PDXP 57026 CG4755 B phyllin pidotimod IGF1R 3480 CG1842 O pifithrin CCNB1, HSP90AA1 891, 3320 CG3510, CG1242 B pindobind HSP90AA1 3320 CG1242 O pioglitazone SER- 462, 64689, 1576, 3726, CG9456, CG7809, CG9438, B PINC1, GORASP1, CYP3A4, 3725, 3727 CG2275, CG2275, JUNB, JUN, JUND CG2275 Piroxicam JUNB, SERPINB3, JUN, 3726, 6317, 3725, 3727 CG2275, CG9456, CG2275, B JUND CG2275 plumbagin GORASP1, CDC2 64689, 983 CG7809, CG5363 B Pluronic p 85 ABCB1, KLHL1 5243, 57626 CG3879, CG17754 O PMPA KLHL1 57626 CG17754 O PMSF KLHL1 57626 CG17754 O posaconazole FAAH 2166 CG6007 B PP-IX CYP3A4 1576 CG9438 O Pragmoline ABCB1 5243 CG3879 O Pravastatin CYP3A4, RAC1, JUNB, 1576, 5879, 3726, 3727, CG9438, CG2248, CG2275, B JUND, ABCB1, CYP4F3, 5243, 4051, 3725, CG2275, CG3879, JUN, PLAT 5327 CG3466, CG2275, CG13744 Prazosin PLAT 5327 CG13744 O PRDL FOXD3, CYP3A4, SMARCB1, 27022, 1576, 6598, 3725, CG3668, CG9438, CG1064, B JUN, PLG 5340 CG2275, CG13744 Prednisone MME, NF2, SERPINC1, 4311, 4771, 462, 5243, CG9565, CG14228, CG9456, O ABCB1, BEST1 7439 CG3879, CG6264 preussin BEST1 7439 CG6264 B Primidone CDK2 1017 CG5363 B Proadifen CYP3A4 1576 CG9438 O Procasil SLC5A5, HSPA1A 6528, 3303 CG32669, CG5436 O Procetofen CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Prodigiosin ABCB1 5243 CG3879 O Prodix GSK3B 2932 CG2621 B Promegestone CYP3A4 1576 CG9438 O Propofol FAAH, CYP3A4 2166, 1576 CG6007, CG9438 B prostaglandin CYP3A4 1576 CG9438 O A1 prostaglandin SSTR1, TFDP1, GSK3B, 6751, 7027, 2932, 6754, CG7285, CG4654, CG2621, B D2 SSTR4, HTR1A 3350 CG7285, CG7485 prostaglandin HTR1A 3350 CG7485 O E1 prostaglandin FGF2, FLT4, SERPINB6 2247, 2324, 5269 CG4608, CG8222, CG9456 O F2alpha prostaglandin CYP4F12, CYP4F8 66002, 11283 CG9438, CG3466 O H2 prostaglandin HSPA4, KHDRBS1 3308, 10657 CG6603, CG4816 O J2 prostaglandins HGF, ATP1B1, CYP24A1 3082, 481, 1591 CG13744, CG9258, CG6042 O prostaglandins G GORASP1, KDR 64689, 3791 CG7809, CG8222 B prostratin CCNT1, CCNT2 904, 905 CG6292, CG6292 O prucalopride HTR4, (CCNT2) 3360, (905) CG6919, (CG6292) O prunustatin A HTR4 3360 CG6919 O Pseudo- HSPA5 3309 CG5436 O hypericin pseudolaric CYP3A4 1576 CG9438 O acid B psilocybin JAG1 182 CG6127 O Psoralens ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O PTAP CYP3A4 1576 CG9438 O PTX-B JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2275 B puerarin JUN 3725 CG2275 B Pugnac JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 B p-XSC KLHL1 57626 CG17754 O Pyrethrins CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O pyrvinium HSP90B1, HSPA5 7184, 3309 CG1242, CG5436 O quercitrin HSPA5 3309 CG5436 O quetiapine HTR1A, CYP3A4 3350, 1576 CG7485, CG9438 O Quicifal CYP3A4 1576 CG9438 O quinupristin- CYP3A4 1576 CG9438 O dalfopristin R 101933 CYP3A4 1576 CG9438 O rabeprazole ABCB1 5243 CG3879 O radester ABCB1 5243 CG3879 O Raloxifene JUND, NCOR1, JUNB, ABCB1, 3727, 9611, 3726, 5243, CG2275, CG7951, CG2275, B BEST1, JUN, CYP3A4 7439, 3725, 1576 CG3879, CG6264, CG2275, CG9438 ramiprilat JUN, JUND, FBN1, JUNB 3725, 3727, 2200, 3726 CG2275, CG2275, CG3936, B CG2275 rebamipide JUNB 3726 CG2275 B reboxetine JAG1 182 CG6127 O remifentanil CYP3A4 1576 CG9438 O renzapride HTR4, (OPRM1) 3360, (4988) CG6919, (CG7285) B repaglinide HTR4 3360 CG6919 O Requip CYP3A4 1576 CG9438 O Revex JUN 3725 CG2275 B Rhodinal OPRK1 4986 CG7285 B Riacon HSPB1, HSPB2 3315, 3316 CG14207, CG14207 B Ribavirin HSPB2 3316 CG14207 B Rifabutin CYP3A4, HSP90AA1, CYP4F3 1576, 3320, 4051 CG9438, CG1242, CG3466 O Riluzole CYP4F3 4051 CG3466 B rimorphin HSPA4 3308 CG6603 O risedronic OPRK1 4986 CG7285 B acid risperidone CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Ritodrine ATP2B2, ATP2B2 491, 491 CG2167, CG2172 O Ritonavir CYP3A7, NF2, CYP27A1, 1551, 4771, 1593, 5243, CG9438, CG14228, CG6042, B ABCB1, CYP24A1, CYP3A4 1591, 1576 CG3879, CG6042, CG9438 rituximab JUND, JUNB, JUN, PDPK1, 3727, 3726, 3725, 5170, CG2275, CG2275, CG2275, B ABCB1 5243 CG1210, CG3879 RMI 12330A ABCB1 5243 CG3879 O Ro 13-8996 CYP27A1 1593 CG6042 B Ro 64-0802 CYP3A4 1576 CG9438 O Robitet ABCB1, SLC5A6, CCND1, 5243, 8884, 595, 5327, CG3879, CG32669, CG9096, O PLAT, FGF2, HGF, TIMM8A, 2247, 3082, 1678, CG13744, CG4608, HSPA4 3308 CG13744, CG1728, CG6603 Rolipram CHAT, MAPT 1103, 4137 CG12345, CG31057 O romidepsin JUND, JUNB, ABCB1, JUN 3727, 3726, 5243, 3725 CG2275, CG2275, CG3879, O CG2275 ropivacaine JUN 1678 CG1728 O Roquefortine CYP3A4 3308 CG6603 O roscovitine HSPB1, HSPB2, GORASP1, 3315, 3316, 64689, 4137, CG14207, CG14207, CG7809, B MAPT, CDK6, CCND2, 1021, 894, 904, CG31057, CG5072, CCNT1, CCND1, CDC2, 595, 983, 1017 CG9096, CG6292, CDK2 CG9096, CG5363, CG5363 rosiglitazone ATP2A2, JUND, JUNB, 488, 3727, 3726, 7248, CG32451, CG2275, CG2275, B TSC1, JUN, GORASP1, 3725, 64689, 3480, CG6147, CG2275, IGF1R, CYP3A4, CIDEA 1576, 1149 CG7809, CG1842, CG9438, CG1975 rosmarinic JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 O acid rosuvastatin ABCB1, KLHL1, SLC22A7 5243, 57626, 10864 CG3879, CG17754, CG8654 O Rozevin JUN, KLHL1, MAPT, CDC2, 3725, 57626, 4137, 983, CG2275, CG17754, CG31057, O ABCB1, JUNB, JUND 5243, 3726, 3727 CG5363, CG3879, CG2275, CG2275 RPR 121056 JUND 10864 CG8654 O Rulid SLC5A5, ABCB1, FLT1 6528, 5243, 2321 CG32669, CG3879, CG8222 B rutecarpine FLT1 983 CG5363 B Rutin ABCB1, HSPA4, HSP90AA1 5243, 3308, 3320 CG3879, CG6603, CG1242 B S 17092-1 PREP, (HSP90AA1) 5550, (1576) CG5355, (CG9438) O S 9788 PREP 6528 CG32669 O S azabisabolene ABCB1 5243 CG3879 O Safingol PPA1 2321 CG8222 O SAHA KPNA2, ADAMTS1, JAK1, 3838, 9510, 3716, 595, CG4799, CG14869, CG1594, O CCND1, JUND, JUN, 3727, 3725, 10628, CG9096, CG2275, TXNIP, DAB1, HSP90AA1, 1600, 3320, 3726 CG2275, CG18745, JUNB CG9695, CG1242, CG2275 saintopin JUNB 3716 CG1594 B Salicin SSTR1, SSTR4, HTR1A 6751, 6754, 3350 CG7285, CG7285, CG7485 B salinomycin HTR1A 10628 CG18745 B salinosporamide A ABCB1 1600 CG9695 O salubrinal EIF2S1, HSPA5 1965, 3309 CG9946, CG5436 B salvin HSPA5 7153 CG10223 B salvinorin A CCNA2 6751 CG7285 B samarium OPRK1 6754 CG7285 B sampatrilat PSMD6 3350 CG7485 O sangivamycin MME 5243 CG3879 O Saquinavir CYP3A7, ABCB1, CYP3A4 1551, 5243, 1576 CG9438, CG3879, CG9438 O Sarasar CYP3A4, KLHL1 1576, 57626 CG9438, CG17754 B sarizotan KLHL1 9861 CG5378 O SB 203580 CCNB1, EGR1, PLAT, 891, 1958, 5327, 114770, CG3510, CG7847, CG13744, B PGLYRP2, PLG, HSPB2, 5340, 3316, 3727, CG14704, CG13744, JUND, SSTR4, JUN, JUNB, 6754, 3725, 3726, CG14207, CG2275, SSTR1, GORASP1, 6751, 64689, 983, 3315, CG7285, CG2275, CG2275, CDC2, HSPB1, HGF, CYP27B1, 3082, 1594, 3350, CG7285, CG7809, HTR1A, ATF2, 1386, 595, 890 CG5363, CG14207, CCND1, CCNA2 CG13744, CG6042, CG7485, CG30420, CG9096, CG3510 SB 207266 HTR4, (CCNA2) 3360, (983) CG6919, (CG5363) O SB 216763 CCND1, GSK3B, GSK3A, 595, 2932, 2931, 488 CG9096, CG2621, CG2621, O ATP2A2 CG32451 SB 225002 HTR1A, SSTR1, SSTR4 3350, 6751, 6754 CG7485, CG7285, CG7285 B SB 415286 GSK3B, RAC1, GSK3A 2932, 5879, 2931 CG2621, CG2248, CG2621 B SB-649915 GSK3A 2931 CG2621 B SB-706375 HTR1A 488 CG32451 B SCH 66712 RPS6KA2 3350 CG7485 O schizandrin B CYP3A4 6751 CG7285 B SCIO-469 HSPB1, HSPB2 3315, 3316 CG14207, CG14207 B scoparone HSPB2 5879 CG2248 B Sediel GORASP1 2931 CG2621 B selamectin HTR1A 3350 CG7485 O Selegiline ABCB1 6196 CG17596 O Serad JUN 1576 CG9438 O sesamin CYP3A4 5243 CG3879 O sevoflurane JUN, PIK3C2A, JUNB, 3725, 5286, 3726, 3727 CG2275, CG11621, CG2275, O JUND CG2275 Sildenafil JUND 5243 CG3879 O silybin CCND3, JUND, JUNB, IGF1R, 896, 3727, 3726, 3480, CG9096, CG2275, CG2275, B JUN, GORASP1, 3725, 64689, 1576, CG1842, CG2275, CYP3A4, CDK2, ABCB1, 1017, 5243, 595 CG7809, CG9438, CG5363, CCND1 CG3879, CG9096 Sizofiran CCND1 3726 CG2275 B sofalcone WNK1 3480 CG1842 O sorafenib KDR, GSK3B, PSMB5, CCND1, 3791, 2932, 5693, 595, CG8222, CG2621, CG12323, B CYP3A4, EIF2S1 1576, 1965 CG9096, CG9438, CG9946 SP 100030 JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2275 O sparfloxacin JUND 2932 CG2621 B spiradoline ABCB1 5693 CG12323 O spiraprilat OPRK1 595 CG9096 B spirogermanium CSE1L 1576 CG9438 O SR 48692 SERPINB1, EGR1 1992, 1958 CG9456, CG7847 B SR 59230A EGR1 3726 CG2275 B SRI 63-154 RAC1 3727 CG2275 B SRIH SSTR3, SSTR4, SSTR1, 6753, 6754, 6751, 6755, CG7285, CG7285, CG7285, O SSTR5, MAGT1, SSTR2 84061, 6752 CG7285, CG7830, CG7285 ST 1481 SSTR2 5879 CG2248 B STA 5326 ABCB1 9159 CG10772 O stachybotrydial RPSA 6753 CG7285 B Stanozolol PLG 6754 CG7285 B Stavudine SERPINC1 6751 CG7285 B SU 1498 CSE1L 6755 CG7285 B SU 5416 KDR (84061), 3791 (CG7830), CG8222 O SU 5614 KDR 6752 CG7285 B SU 6656 KDR 5243 CG3879 O SU 6668 RAC1 3921 CG14792 O SU 9516 CDK2, CCND1 1017, 595 CG5363, CG9096 B Sucralfate CCND1 1434 CG13281 O Sufentanil PHC2 3791 CG8222 O Sulem OPRM1 3791 CG8222 O Sulfamerazine HSPA4 3791 CG8222 O Sulfamethazine MYB 5879 CG2248 B sulfamide CYP3A4 3791 CG8222 O Sulfaphenazole JUNB, JUND, CYP4F3, 3726, 3727, 4051, 3725, CG2275, CG2275, CG3466, B JUN, CYP3A5 1577 CG2275, CG3466 Sulfoximine JUN 3308 CG6603 O Sulindac CCND1, TSC1, ABCB1 595, 7248, 5243 CG9096, CG6147, CG3879 B sultopride ABCB1 3726 CG2275 B Sumatriptan ABCB1 3727 CG2275 B sunitinib KDR, CYP3A4 3791, 1576 CG8222, CG9438 B sural MMEL1, RPSA 79258, 3921 CG9565, CG14792 B T 0901317 RPSA 7248 CG6147 O TAC 101 JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2275 O Tacrolimus CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Tamogel CCND2, CYP3A4 894, 1576 CG9096, CG9438 O tamsulosin CYP3A4 1576 CG9438 O tandospirone CYP3A4, HTR1A 1576, 3350 CG9438, CG7485 B Tangeretin HTR1A 3725 CG2275 B tanshinone ABCB1, CYP3A4 5243, 1576 CG3879, CG9438 O tariquidar CYP3A4 894 CG9096 B Taseron ABCB1 1576 CG9438 O Taurolin HTR1A 146 CG18741 O TAXOTERE KLHL1, GLA, WNK1, CCND1, 57626, 2717, 65125, CG17754, CG5731, CG7177, O CYP4F3, RAC1, ABCB1, 595, 4051, 5879, 5243, CG9096, CG3466, CCNB1, TUBA1B, 891, 10376, 983, 1576 CG2248, CG3879, CG3510, CDC2, CYP3A4 CG1913, CG5363, CG9438 tazarotene TSC1, APC 7248, 324 CG6147, CG6193 B TBDZ CYP4F3, HSPA5, HSPA4 4051, 3309, 3308 CG3466, CG5436, CG6603 B TBHQ JUND, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2275 O TCDD JUN, PLAT, CYP3A7, PPIF, 3725, 5327, 1551, 10105, CG2275, CG13744, CG9438, B ABCB1, CYP27B1, 5243, 1594, 4051 CG2852, CG3879, CYP4F3 CG6042, CG3466 Tegafur WNK1, MAGT1 65125, 84061 CG7177, CG7830 B tegaserod HTR4, (MAGT1) 3360, (5327) CG6919, (CG13744) O telithromycin HTR4 1551 CG9438 O telmisartan CYP3A4 10105 CG2852 O temozolomide EIF2S1, CDC2 1965, 983 CG9946, CG5363 B temsirolimus CCND1, CYP3A4 595, 1576 CG9096, CG9438 O Teniposide TOP2B, JUN 7155, 3725 CG10223, CG2275 O Terfenadine JUN 1576 CG9438 O Teriparatide PLG, BEST1, HSPA4 5340, 7439, 3308 CG13744, CG6264, CG6603 B Tetraprenol HSPA4 595 CG9096 B TG101209 TBXAS1 1576 CG9438 O thalicarpine JAK2 7155 CG10223 B Thapsigargin CDK2, HSPB1, HSPA4, 1017, 3315, 3308, 3316, CG5363, CG14207, CG6603, O HSPB2, RPSA, HSP90B1, 3921, 7184, 3350, CG14207, CG14792, HTR1A, HSPA1A, JUN, 3303, 3725, 3304, 5243, CG1242, CG7485, HSPA1B, ABCB1, HSPA5, 3309, 3306, 2932, CG5436, CG2275, CG31449, HSPA2, GSK3B, X1 7494 CG3879, CG5436, CG5436, CG2621, CG9415 Theaflavin JUND, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2275 B Thiazolidinediones NRF1, CYP3A4, BEST1, 4899, 1576, 7439, 595 CG3114, CG9438, CG6264, B CCND1 CG9096 thiocoraline CCND1 7494 CG9415 B thioridazine CYP3A4 3727 CG2275 B Thiorphan MME, ECE1 4311, 1889 CG9565, CG9565 B thromboxane ECE1 4899 CG3114 B B2 thulium SERPINC1 1576 CG9438 O thymalfasin ABCB1, JUND, JUN, JUNB 5243, 3727, 3725, 3726 CG3879, CG2275, CG2275, O CG2275 Thymopentin JUNB 4311 CG9565 O thymoquinone MME 1889 CG9565 O Ticlopidine SERPINC1, CYP4F3 462, 4051 CG9456, CG3466 B Tilidine CYP3A4, CSE1L, ABCB1 1576, 1434, 5243 CG9438, CG13281, CG3879 B tipifarnib GORASP1, ABCB1 64689, 5243 CG7809, CG3879 O tipranavir ABCB1 64689 CG7809 B tirilazad CYP3A4 462 CG9456 B TKI-31 CYP3A4 4051 CG3466 B Tmndga KDR 1576 CG9438 O TMPN ABCB1 1434 CG13281 O Toddalin JUN, HSPB1, GORASP1 3725, 3315, 64689 CG2275, CG14207, CG7809 O Todralazine GORASP1 1576 CG9438 O tofisopam PREP 1576 CG9438 O Tolterodine CYP4F3, CSE1L 4051, 1434 CG3466, CG13281 O topiramate CSE1L 3725 CG2275 B Topotecan HSPA4, CYP3A4, ABCB1 3308, 1576, 5243 CG6603, CG9438, CG3879 B Toremifene ABCB1 5550 CG5355 O Toxaphene SERPINC1 1576 CG9438 O Tramadol TSC1 4051 CG3466 B Tramat HSP90B1, MAPT, CCND1, 7184, 4137, 595, 1761, CG1242, CG31057, CG9096, O DMRT1, HSP90AA1 3320 CG11094, CG1242 trandolapril HSP90AA1 462 CG9456 B Trapidil PLAT 7248 CG6147 O trapoxin A FGF2 5243 CG3879 O trastuzumab CCNA2, CCND1, PDPK1, 890, 595, 5170, 127933, CG3510, CG9096, CG1210, B UHMK1, TOP2A, CDK2, 7153, 1017, 4851, CG3162, CG10223, NOTCH1, RAC1, CDK6 5879, 1021 CG5363, CG3936, CG2248, CG5072 Trazodone CDK6 595 CG9096 B Tremode ABCB1 5170 CG1210 B triazolam CYP3A4 127933 CG3162 O triazolobenzodiazepines CYP3A4 7153 CG10223 B tributylstannane PLAT 1017 CG5363 B trichostatin A CYP4F3 4851 CG3936 B trichostatins CDK6, CCND1, CDK4 1021, 595, 1019 CG5072, CG9096, CG5072 O Trifluoperazine ABCB1, EGR1 5243, 1958 CG3879, CG7847 O trioctyl MYBL2, TFDP1, APC, MYB 4605, 7027, 324, 4602 CG9045, CG4654, CG6193, O phosphine oxide CG9045 Triolein MYB 595 CG9096 B triptolide JUND, JUNB, JUN, GORASP1, 3727, 3726, 3725, 64689, CG2275, CG2275, CG2275, O HSPA4, GSK3B 3308, 2932 CG7809, CG6603, CG2621 TRK 820 GSK3B 4602 CG9045 B troglitazone CYP3A7, CYP3A4, JUND, 1551, 1576, 3727, 4602, CG9438, CG9438, CG2275, B MYB, JUN, EGR1, CDC2, 3725, 1958, 983, CG9045, CG2275, JUNB, CDK4, CDK2, 3726, 1019, 1017, 1021, CG7847, CG5363, CG2275, CDK6, CCND1, CCNE1, 595, 898, 896, 894 CG5072, CG5363, CCND3, CCND2 CG5072, CG9096, CG3938, CG9096, CG9096 Troleandomycin CYP4F3, CYP3A4, CYP3A7 4051, 1576, 1551 CG3466, CG9438, CG9438 B tropisetron HTR4, (CYP3A7) 3360, (1021) CG6919, (CG5072) O Trospium HTR4 595 CG9096 B chloride Tunicamycin CCNA2, HSPA4, HSPA5, 890, 3308, 3309, 4899, CG3510, CG6603, CG5436, O NRF1, ABCB1, EIF2S1, 5243, 1965, 7184, CG3114, CG3879, HSP90B1, CCND1 595 CG9946, CG1242, CG9096 tylophorine JUND, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2275 O Tylox OPRM1, ABCB1 4988, 5243 CG7285, CG3879 O tyrphostin IGF1R, JUND, RAC1, RPS6KA1, 3480, 3727, 5879, 6195, CG1842, CG2275, CG2248, B AG-490 EGR1, JUN, JUNB, 1958, 3725, 3726, CG17596, CG7847, CCND1, RAC1, ADAMTS4, 595, 5879, 9507, 3717 CG2275, CG2275, CG9096, JAK2 CG2248, CG14869, CG1594 tyvelose JAK2 6195 CG17596 O U 0126 FCN2, GORASP1, HGF, 2220, 64689, 3082, 595, CG555, CG7809, CG13744, B CCND1, RPSA, PLAT, JUND, 3921, 5327, 3727, CG9096, CG14792, ADAMTS4, CCNA2, 9507, 890, 3726, 1019, CG13744, CG2275, JUNB, CDK4, EGR1, ABCB1, 1958, 5243, 3725, CG14869, CG3510, CG2275, JUN, EGR2 1959 CG5072, CG7847, CG3879, CG2275, CG7847 U 69593 EGR2 9507 CG14869 O Ubizol GORASP1, HSPA4 64689, 3308 CG7809, CG6603 B UH 301 HSPA4 1019 CG5072 O Usaf B-12 CCNA2, SERPINC1, PLG, 890, 462, 5340, 3309, CG3510, CG9456, CG13744, O HSPA5, JUND, PLAT, 3727, 5327, 6573, 1965, CG5436, CG2275, SLC19A1, EIF2S1, HSPA4, 3308, 2200, 3726, CG13744, CG14694, FBN1, JUNB, JUN 3725 CG9946, CG6603, CG3936, CG2275, CG2275 USAN HSPA8, CCND1, MME, SER- 3312, 595, 4311, 6317, CG31449, CG9096, CG9565, B PINB3, CDK2, TMSB4X, 1017, 7114, 3308, CG9456, CG5363, HSPA4, KLHL1, HGF 57626, 3082 CG4944, CG6603, CG17754, CG13744 Valproic Acid GSK3B, JUNB, JUN, TSC1, 2932, 3726, 3725, 7248, CG2621, CG2275, CG2275, O JUND, HTR1A, MME, 3727, 3350, 4311, CG6147, CG2275, NOTCH1, MMEL1, CCND1, 4851, 79258, 595, 1576, CG7485, CG9565, CG3936, CYP3A4, NF2, APC, 4771, 324, 3082, CG9565, CG9096, HGF, HSPA4, HSPA5, 3308, 3309, 5243, 1600, CG9438, CG14228, ABCB1, DAB1, PREP 5550 CG6193, CG13744, CG6603, CG5436, CG3879, CG9695, CG5355 valsartan PREP 4771 CG14228 B valspodar CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O vandetanib KDR, ABCB1 3791, 5243 CG8222, CG3879 O vapreotide SSTR2, SSTR1 6752, 6751 CG7285, CG7285 O venlafaxine SSTR1 5550 CG5355 O Verapamil PLAT, MAPT, VHLL, ABCB1, 5327, 4137, 391104, CG13744, CG31057, CG13221, B CYP3A4, KLHL1 5243, 1576, 57626 CG3879, CG9438, CG17754 verlukast ABCB1, KLHL1 5243, 57626 CG3879, CG17754 O verrucosidin KLHL1 5327 CG13744 O versipelostatin HSPA5 4137 CG31057 B VGA1155 KDR, FLT1 3791, 2321 CG8222, CG8222 O Vigil FLT1 1576 CG9438 O vincaleukoblastine CYP3A4 57626 CG17754 O vincristine HSPB2, RPSA, EIF2S1, 3316, 3921, 1965, 1678, CG14207, CG14792, CG9946, O TIMM8A, TXNL1, CYP3A4, 9352, 1576, 891, CG1728, CG5495, CCNB1, ABCB1, KLHL1, 5243, 57626, 3315, 27022 CG9438, CG3510, HSPB1, FOXD3 CG3879, CG17754, CG14207, CG3668 Vindesine FOXD3 1678 CG1728 O vinorelbine GLA, CYP4F3 2717, 4051 CG5731, CG3466 O Visken CYP4F3 891 CG3510 B Viviq IK 27022 CG3668 B voriconazole CYP3A4, MAPT 1576, 4137 CG9438, CG31057 B vorozole MAPT 4051 CG3466 B vulnibactin SERPINB1 3350 CG7485 O Wakil FURIN 50846 CG4637 O Warfarin CYP4F2, CYP3A4, CSE1L 8529, 1576, 1434 CG3466, CG9438, CG13281 B Wartmannin JUNB, JAK2, RAC1, MSN, 3726, 3717, 5879, 4478, CG2275, CG1594, CG2248, B GSK3B, JUN, JUND, 2932, 3725, 3727, CG10701, CG2621, CCNB1, FGF2, CYP3A4, 891, 2247, 1576, 595, CG2275, CG2275, CG3510, CCND1, FGF7, ETV5, 2252, 2119, 64689, CG4608, CG9438, GORASP1, HGF 3082 CG9096, CG4608, CG6892, CG7809, CG13744 WAY 100635 HGF 891 CG3510 B Wogonin JUND, JUN, JUNB 3727, 3725, 3726 CG2275, CG2275, CG2275 B WR 1065 JUNB 2252 CG4608 B WS 79089B GORASP1 2119 CG6892 O xanthohumol CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O Xaxa PLAT, MLH1, JUND, SERPINC1, 5327, 4292, 3727, 462, CG13744, CG11482, CG2275, O JUN, GORASP1, 3725, 64689, 595, CG9456, CG2275, CCND1, JUNB, ABCB1 3726, 5243 CG7809, CG9096, CG2275, CG3879 ximelagatran ABCB1 4292 CG11482 B Xylit ABCB1 3727 CG2275 B Y 27632 JUND, RAC1, JUNB, JUN 3727, 5879, 3726, 3725 CG2275, CG2248, CG2275, B CG2275 YM-201627 JUN 3726 CG2275 B YM-231146 FGF2 5243 CG3879 O zacopride HTR4, (KDR) 3360, (5243) CG6919, (CG3879) O zafirlukast HTR4 5550 CG5355 O ZD 4190 CYP3A4 3727 CG2275 B zeaxanthin KDR 5879 CG2248 B Zeldox ABCB1 3726 CG2275 B zileuton CYP3A4 3725 CG2275 B Zimco JUND, JUN, JUNB 3727, 3725, 3726 CG2275, CG2275, CG2275 O zincov PPA1, MME 5464, 4311 CG4634, CG9565 O ZK 112993 MME 5243 CG3879 O ZM323881 RPSA 1576 CG9438 O zopiclone KDR 4051 CG3466 B ZSTK474 CYP3A4 3727 CG2275 B Zymosan PSMC1, MBL2 5700, 4153 CG5289, CG7763 B In preferred embodiments, the present invention is defined as follows:

Definition 1. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.

Definition 2. The method of reducing weight and/or body fat in a subject or to treat obesity comprising the administration of an antagonist of one or more of the genes selected from CG30184, CG10369, CG32401, CG2374, CG8693, CG14909, CG13299, CG7847, CG30462, CG30462, CG15169, CG1650, CG6577, CG30491, CG4373, CG10407, CG2198, CG6356, CG5744, CG9506, CG31169, CG1728, CG9220, CG15625, CG5550, CG13088, CG13188, CG14968, CG1503, CG1666, CG14869, CG2702, CG2984, CG4394, CG9922, CG14529, CG17781, CG17781, CG9153, CG15178, CG5641, CG3879, CG15579, CG1422, CG6299, CG8107, CG7103, CG10617, CG30360, CG32971, CG32336, CG31036, CG12602, CG9676, CG1433, CG1100, CG31697, CG7095, CG2165, CG10230, CG10916, CG3274, CG18767, CG5072, CG3396, CG15582, CG16826, CG6788, CG9487, CG1888, CG4637, CG15162, CG5719, CG2254, CG4695, CG14936, CG17867, CG15646, CG5402, CG15095, CG8250, CG18030, CG14303, CG14164, CG14677, CG12105, CG17440, CG32459, CG11404, CG8954, CG13138, CG9056, CG12997, CG12997, CG5436, CG14330, CG10809, CG1622, CG3893, CG1112, CG31690, CG12664, CG13679, CG17556, CG10062, CG31744, CG9760, CG1555, CG14375, CG32170, CG4271, CG32234, CG7287, CG14341, CG30486, CG31692, CG31421, CG5467, CG30065, CG9086, CG1688, CG17026, CG4415, CG10343, CG15388, CG13984, CG3313, CG13116, CG4662, CG6919, CG17841, CG30411, CG9053, CG1180, CG14166, CG13125, CG13344, CG1490, CG2867, CG5591, CG14362, CG1531, CG15390, CG6689, CG14234, CG14265, CG5674, CG3917, CG8257, CG9028, CG1722, CG18402, CG7082, CG11797, CG3663, CG16704, CG31172, CG31219, CG1363, CG6721, CG5688, CG8527, CG13137, CG6612, CG6947, CG7737, CG1705, CG14704, CG10300, CG3597, CG3425, CG2540, CG6856, CG12259, CG4583, CG3843, CG9634, CG3809, CG9295, CG9485, CG11555, CG11601, CG14095, CG10166, CG2852, CG14164, CG14164, CG2898, CG3162, CG6603, CG8721, CG17742, CG14127, CG8665, CG9438, CG32113, CG32353, CG4957, CG33558, CG11570, CG32669, CG11575, CG30271, CG7830, CG31061, CG2076, CG17596, CG6824, CG17921, CG12875, CG13020, CG13972, CG13673, CG10772, CG8079, CG13127, CG9144, CG8979, CG7097, CG11768, CG10632, CG14903, CG1874, CG33466, CG3367, CG4851, CG17985, CG31229, CG3260, CG13023, CG11125, CG17184, CG31812, CG13360, CG30075, CG30183, CG7485, CG5495, CG5495, CG7065, CG13202, CG7779, CG9322, CG7091, CG16758, CG5071, CG4920, CG1516, CG9554, CG10101, CG3004, CG7796, CG10152, CG18741, CG8444, CG11425, CG10128, CG10542, CG11878, CG14434, CG12345, CG2091, CG31459, CG13319, CG7177, CG7776, CG15005, CG31605, CG7213, CG17283, CG18268, CG3017, CG7567, CG32091, CG9695, CG8222, CG1515, CG8256, CG1975, CG32467, CG3817, CG4038, CG6193, CG1572, CG8117, CG3526, CG7099, CG18525, CG9198, CG30470, CG17273, CG31439, CG1387, CG9952, CG6580, CG10840, CG13221, CG8202, CG8786, CG7199, CG11663, CG12683, CG31161, CG8009, CG17202, CG1683, CG17335, CG33204, CG14694, CG11229, CG16836, CG12209, CG18414, CG13475, CG11621, CG13332, CG11756, CG11133, CG18586, CG4944, CG3213, CG4152, CG6147, CG8515, CG5827, CG12691, CG8308, CG13807, CG2260, CG30004, CG4247, CG4247, CG5739, CG4202, CG4264, CG5245, CG13707, CG3523, CG10686, CG9565, CG4111, CG14673, CG31132, CG5355, CG32149, CG8443, CG17461, CG8190, CG13744, CG9258, CG6043, CG1759, CG8534, CG14792, CG8451, CG8654, CG12806, CG14938, CG9399, CG10542, CG13168, CG31845, CG6277, CG17819, CG2818, CG1688, CG13868, CG17736, CG7546, CG31693, CG12897, CG2146, CG3440, CG3696, CG12426, CG18319, CG18279, CG18279, CG3054, CG2145, CG3825, CG9781, CG13423, CG12030, CG14911, CG3911, CG6122, CG7206, CG8566, CG30476, CG9470, CG6127, CG5381, CG12505, CG1279, CG32140, CG12184, CG31364, CG1963, CG5484, CG4634, CG9748, CG32442, CG1921, CG18740, CG1242, CG9946, CG11121, CG3497, CG6817, CG30080, CG1171, CG11430, CG10691, CG13281, CG11352, CG3839, CG14368, CG14024, CG9936, CG11505, CG11906, CG1263, CG14011, CG11339, CG12015, CG30389, CG17331, CG15432, CG15507, CG14842, CG3906, CG17754, CG5289, CG5378, CG5625, CG6156, CG13243, CG8239, CG1821, CG7762, CG3108, CG8053, CG3605, CG4207, CG8431, CG9098, CG5270, CG5595, CG6064, CG6967, CG7134, CG7549, CG6892, CG10687, CG10712, CG11981, CG12770, CG15599, CG18563, CG7770, CG6322, CG3806, CG3980, CG6054, CG7292, CG3992, CG2998, CG8337, CG13194, CG5147, CG16903, CG11202, CG10084, CG12323, CG31484, CG6949, CG7352, CG10728, CG11376, CG32210, CG7109, CG8615, CG9160, CG8298, CG15115, CG1965, CG12595, CG15321, CG6009, CG11267, CG4453, CG3971, CG17255, CG32791, CG14016, CG14016, CG1740, CG32667 or an ortholog thereof.

Definition 3. The method according to definition 1 or 2, characterized in that the compound or antagonist is administered in a effective therapeutic dose.

Definition 4. The method of any one of definitions 1 to 3, characterized in that the compound is administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or intraperitoneal, transdermal, transmucosal or inhalational.

Definition 5. The method of any one of definitions 1 to 4, characterized in that the subject is mammal, preferably a human.

Definition 6. The method of any one of definitions 1 to 5, characterized in that the compound or antagonist is provided in a medicament.

Definition 7. The method of any one of definitions 1 to 6, characterized in that the compound or antagonist is provided together with a pharmaceutically acceptable carrier or buffer.

Definition 8. The method of any one of definitions 1 to 6, characterized in that the compound or antagonist is administered in a dosage of between 0.01 mg/kg and 1 g/kg.

Definition 9. Use of a compound as defined in definitions 1 or an antagonist as defined in definition 2, preferably further defined as in any one of definitions 3 to 8, for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat or prevent obesity in a subject.

Further preferred definitions are given in the claims.

The present invention is further illustrated by the following figures and examples.

FIGURES

FIG. 1. Genome-wide RNAi screen for obesity factors in adult Drosophila in vivo.

(A) Schematic of the screen design: virgin heat shock inducible (Hsp70-GAL4;Tub-GAL80ts) females were crossed to UAS-RNAi transgenic males. RNAi was induced 2 days post-eclosure and again after 4 days. One week after RNAi-induction triglyceride and protein levels were determined in a 96-well format and compared to internal controls: non-induced progeny of the same cross. (B) The system was capable of detecting developmental and sex-specific fat storage patterns, and (C) a variety of feeding conditions. Data are shown as mean triglyceride content +/−sem. n=8. (D,E) Double blinded retrieval of primary screen results for positive control lines predicted to (D) reduce or (E) increase triglyceride levels. (F) Z-score distribution of the primary screen results. Red lines indicate Z-scores of +1.65 above and −1.65 below baseline levels. (G) Gene ontology analysis with a level 5 cut-off for biological processes for all annotated genes with Z-scores above or below ±1.65 after three rounds of testing. See also FIGS. 2 and 4.

FIG. 2. Basal triglyceride and protein contents in Drosophila. Related to FIG. 1.

(A) Triglyceride content of w1118 Drosophila strain measured throughout development using a medium-throughput 96-well plate based system with a colorimetric determination endpoint. (B) Protein content of w1118 Drosophila measured with the same experimental set-up. Data in a and b are shown as mean triglyceride content +/−s.e.m. n=5-8. (C) Individual triglyceride and protein content in 80 different sets of 8 male flies each measured 2 to 4 days after enclosure. Measurement was made to validate the medium throughput experimental system designed for the genome-wide screen. (D) Pie chart summarizing the most depleted functional classifications using gene ontology for biological processes for all annotated genes with Z-scores in excess of +/−1.65 through three rounds of testing.

FIG. 3. Tissue-specific regulation of fat storage.

(A) Heat-map of changes in triglyceride for primary screen hits crossed to nsyb-GAL4 (pan-neuronal), oe-GAL4 (oenocyte), C57-GAL4 (muscle), and ppl-GAL4 (fat-body) drivers. Changes are relative to control RNAi-lines and isogenic w1118 flies crossed to the respective GAL4 drivers. (B-E) Left panels show the mean changes in triglycerides after tissue-specific knockdown for the top-scoring fat-enhancing (red lines) and fat-depleting (blue lines) genes in each tissue category. Note the marked neuronal specificity, an overlap in fat-body and oenocyte responses, and a relative lack of specificity for top-scoring muscle responsive genes. Right panels summarize gene-ontology analysis for each category (level 5 cut-off for biological processes). Intensity of the red reflects increased significance of the GO term.

FIG. 4. Interaction network for candidate obesity genes. Related to FIG. 1.

The interaction network was assembled using Cytoscape 2.6.2 based on interactions retrieved from STRING, DROIDB, and BIOGRID. Datasets consisted of yeast-2-hybrid, text-mining, and database annotations (e.g. KEGG). Assembly of the visual layout was performed using manual modification of an automated forcedirected layout. Insets highlight the location of both the hedgehog and insulin signaling pathways.

FIG. 5. Analysis of tissue-specificity reveals hedgehog signaling as a fat-body specific regulator of triglyceride levels.

Triglyceride responses of candidate genes. Changes in adiposity in RNAi lines with the most tissue-restricted responses in the (A) pan-neuronal, (B) muscle, (C) oenocyte, and (D) fat-body compartments. (E) Heat-map of adiposity observed in UAS-RNAi transgenic fly lines targeting available annotated hedgehog and notch pathways. Changes are relative to averages of control RNAi-lines and w1118 flies crossed to the respective GAL4 drivers. Genes are grouped according to their role as either positive (+) or negative (−) effectors, or as mediators of ligand processing and release (Lp). (F) Representative triglyceride changes in response to ppl-GAL4 driven knockdown of effectors of hedgehog signaling and (G) repressors of the pathway. Data are presented as mean±s.e.m., n=4. * p<0.05. See also FIG. 6.

FIG. 6. Tissue-specificity of hedgehog and OxPhos pathway triglyceride changes. Related to FIG. 5.

(A) Correlation analysis of triglyceride levels in RNAi lines targeting hedgehog signaling crossed to the tissue-specific drivers nsyb-GAL4 (pan-neuronal), oe-GAL4 (oenocyte), C57-GAL4 (muscle), and ppl-GAL4 (fat-body). Tissue-specific triglyceride changes (y-axes) are correlated with those observed using the inducible ubiquitous Hsp70-GAL4;Tub-GALBOts (x-axis). (B) Triglyceride changes in ppl-GAL4 driven UAS-RNAi transgenic lines targeting hedgehog specific ligand processing and release genes. (C) Heat-map of the adiposity of UAS-RNAi transgenic fly lines targeting the members of the gene ontology category oxidative phosphorylation. Changes in adiposity were in response to tissue-specific silencing using the drivers nsyb-GAL4 (pan-neuronal), oe-GAL4 (oenocyte), C57-GAL4 (muscle), and ppl-GAL4 (fat-body). Changes, are relative to averages of control RNAi-lines and w1118 flies crossed to the respective GAL4 lines. (D) Triglyceride responses of the same oxidative phosphorylation targeting RNAi-transgenic lines to heat-shock induced ubiquitous knockdown. Data are presented as mean±s.e.m. n=4.

FIG. 7. aP2-Sufu mice display white adipose tissue specific lipoatrophy.

(A) aP2-SufuKO mice are born healthy and at Mendelian ratios. (B) NMR imaging of an aP2-SufuKO mouse and a Sufu-expressing littermate control. (C) Cross-section at the level of the scapulae show unaltered brown adipose depots (yellow dashed lines). (D) PCR revealed robust deletion of the Sufu allele (Sufu 4-8) in both BAT and WAT depots. Minor deletion was detected in skeletal muscle, lung, and the spleen. (E) Tissue dissection white adipose tissue (WAT; upper panel) and brown adipose tissue (BAT; lower panel) revealed fully developed brown adipose depots despite severely compromised white adipose tissue depots in aP2-SufuKO mice. Dashed lines mark white adipose tissue. (F,G) Representative H&E stained sections of (F) brown (BAT) and (G) white (WAT) adipose tissues from aP2-SufuKO and control littermate mice. (H,I) Quantitative RT-PCR of the transcriptional hedgehog targets Gli1, Gli2, Ptch1 and Ptch2 confirmed activation of hedgehog signaling in both (H) WAT and (I) BAT of aP2-SufuKO mice relative to targeted (flox) and aP2-cre (cre) transgenic littermate controls. Data are presented as mean±s.e.m. n=5 mice per group. * p<0.05. See also FIG. 8.

FIG. 8. IBMX and dexamethasone dependence of hedgehog signaling in adipocytes and generation of lipoatrophic Sufu mutant mice related to FIG. 7.

(A) Oil Red O staining of 3T3-L1 cells induced with minimal (Insulin/Troglitazone) or complete (Insulin/Troglitazone/IBMX/Dex) differentiation cocktails in the absence (control) or presence (SAG) of the hedgehog agonist SAG (200 nM). One experiment representative of 5 repeats is shown. (B) Quantitative RT-PCR monitoring of hedgehog pathway activation with the target genes Gli1 and Ptch1 confirmed activation by SAG and abrogation of hedgehog induction in the presence IBMX and Dex. (C) To establish an in vivo model to assess hedgehog effects on adipose biology, a targeting strategy was used to generate mice with a conditional Sufu allele. The conditional allele encorporates two Cresensitive loxP sites flanking exons 4-8 of the Sufu open reading frame. Numbered boxes indicate exons. (D) White (perigonadal) adipose tissue, interscapular brown adipose tissue and muscle (soleus and gastrocnemius) masses were determined in aP2-SufuKO mice at 8 weeks of age. Data from littermates that carry the floxed allele (flox) or aP2-Cre (cre) are shown as controls. Data are presented as mean±s.e.m. n=6 mice per group. ** p<0.01. (E) H&E stained sections of skin highlight a clear reduction in cutaneous adipose tissue. (F) White adipocyte size distributions in perigonadal fat pads taken from 4 week old male aP2-SufuKO mice and littermate floxed (flox) and aP2-Cre (cre) controls. Measurements were made by morphometry on >10,000 (KO) and >35,000 (controls) cells per animal using a combination of scanning of H&E stained interval sectioned adipose tissue (3 per mouse) and subsequent software assisted morphometric analysis (G) Total white adipocyte cell numbers in 4-8 week old male aP2-SufuKO mice and littermate floxed (flox) and aP2-Cre (cre) controls. Data are presented as mean±s.e.m, n=5.

FIG. 9. Loss of weight in Vandetanib administered mice. C57BL6/J DIO mice were administered 40/mg/kg/day by oral gavage. The mice were weighed daily and the values were expressed as a percentage of the starting weight (day 1). By day 13 of administration there was significant loss of weight in the vandetanib administered group compared to the vehicle control (p<0.05; unpaired student t test) which was maintained for the duration of the experiment. Error bars represent standard error of the mean.

FIG. 10. Lower fasting glucose levels in vandetanib administered mice. On day 7 of vandetanib administration the mice were subjected to an Insulin Tolerance Test. Briefly the mice were fasted for 2 hours. Blood was collected at time 0 prior to injection of insulin. Blood was collected at 15, 30, 45 and 60 minutes after injection to measure the glucose response. Although the insulin response was similar in both groups, the vandetanib administered mice exhibited lower fasting blood glucose levels compared to the controls (p<0.05; unpaired student t test). Error bars represent standard error of the mean.

FIG. 11. Oral glucose tolerance test (oGTT) in vandetanib administered mice compared to vehicle controls. Mice were fasted overnight and on day 35 a blood sample was taken to measure the fasting glucose levels (time 0). The mice were administered glucose, blood was collected and the glucose levels were measured 15, 45 and 60 minutes after glucose administration. Vandetanib administered mice show an improved glucose response compared to the vehicle administered group 15, 45 and 60 minutes after glucose administration (p<0.05; unpaired student t test). Error bars represent standard error of the mean.

FIG. 12. Measurement of perigonadal fat pad weights. The vandetanib and vehicle administered mice were sacrificed on day 38 of administration. The perigonadal fat pads were dissected and the weight (grams) was expressed as a ratio compared to body length (cm). Each point on the graph represents the average weight (g) of the two perigonadal fat pads from each mouse expressed as a ratio to body length (cm). The vandetanib administered mice have a proportionally lower fat pad mass compared to vehicle controls (p<0.05; unpaired student t test). Error bars represent standard error of the mean.

FIG. 13. Loss of weight in dasatininb administered mice. C57BL6/J DIO mice were administered 5/mg/kg/day for 27 days. The mice were weighed daily and the values were expressed as a percentage of the starting weight (day 1). On day 28 there was significant loss of weight in the dasatinib administered group compared to the vehicle control (p<0.001; unpaired student t test). Error bars represent standard error of the mean.

FIG. 14. Improved insulin response in dasatinib administered mice on day 15 of administration. An oral glucose tolerance test (oGTT) was performed in mice which were fasted overnight. A blood sample was taken to measure the fasting glucose levels (time 0). The mice were administered glucose, blood was collected and the glucose levels measured 15, 30, 45 and 60 minutes after glucose administration. Dasatinib administered mice show an improved early response to glucose administration at the 15 minute (p<0.01), 30 and 45 minute (p<0.05) time point compared to the vehicle administered group. Error bars represent standard error of the mean.

FIG. 15. Improved insulin response in dasatinib administered mice on day 29. An oral glucose tolerance test (oGTT) was performed in mice which were fasted overnight. A blood sample was taken to measure the fasting glucose levels (time 0). The mice were administered glucose, blood was collected and the glucose levels measured 15, 45 and 60 minutes after glucose administration. The values obtained for each mouse was expressed as percentage of the starting glucose levels (t=0). Dasatinib administered mice show improved glucose clearance 45 (p<0.05) and 60 minutes (p<0.01) after glucose administration compared to the vehicle administered group (Student t-test; p<0.05). Error bars represent standard error of the mean.

EXAMPLES Example 1 In Vivo High Throughput Screen for Obesity Genes in Drosophila

To identify candidate obesity genes, we performed a genome-wide RNAi transgenic-RNAi screen for fat content in adult Drosophila using a heat shock-inducible Hsp70-GAL4 system (FIG. 1A). Triglycerides, the major lipid storage form in animals, were chosen as a direct measure of fly adiposity. Total fly triglyceride levels were measured by colorimetric determination and normalized to protein (FIG. 1A). Using this experimental set-up, we were able to track triglyceride changes throughout development as well as to clearly distinguish sex-specific differences in fat content (FIG. 1B; FIG. 2A,B) and those induced by varying nutrient availability (FIG. 1C). After the first round of screening, double-blinded analysis of RNAi lines targeting genes previously reported to regulate fat content revealed lipid alterations consistent with expected lean (FIG. 1D) and obese (FIG. 1E) phenotypes. Included were the LSD (Lipid Storage Droplet) and LPD (LiPid Depleted) genes as well as the Drosophila insulin like peptides (Ilp's), the glucagon homologue akh and its receptor akhr, as well as adipose (adp), bubblegum (bbg), and the Drosophila SREBP homologue, HLH106 (Gronke et al., 2007; Hader et al., 2003; Min and Benzer, 1999).

Example 1.1 Genome-Wide Obesity Screen in Adult Drosophila

We tested the fat regulatory potential of 11,594 different UAS-RNAi transgenic lines corresponding to 10,812 transgene constructs and 10,489 distinct ORFs, in the adult fly. Primary screening involved three rounds of testing where candidates with a Z-score greater than 1.65 were selected for retesting (FIG. 1A,F). After three rounds of selection 516 RNAi-transgenic lines remained, 462 of which had only single primary target predictions (S19 score ≧0.8 and ≦6 CAN repeats as described by (Dietzl et al., 2007). Important for the translation of these findings into the mammalian context, 319 of 516 (62%) have human orthologues according to InParanoid, OrthoMCL, and Ensembl databases.

Gene ontology (GO) based pathway analysis for biological process revealed enrichment of gene sets involved in cell fate determination, cellular protein metabolic processes, signal transduction, intracellular transport, and regulation of smoothened signaling. Pathways most depleted during the screen, i.e. those not relevant to fat regulation, included genes regulating behavior, cell cycle, organelle organization and biogenesis, locomotory behavior, and chromosome organization. A network interaction assembly based on yeast-2-hybrid, text-mining, and pathway database information on the Drosophila hits and their mammalian orthologues revealed an interaction network map (FIG. 4) highlighting genes of development, nutrient transport, cell cycle regulation, the proteasome, protein translation, and chromatin remodeling. Of particular interest, the candidate gene list included a number of potential regulators of feeding control. For instance, six odorant and two gustatory receptor genes were targeted (Odorant receptors 10a, 56a, 65a, 67a, 83cd, and CG10407; gustatory receptors 98b and 36b). Also, the dopamine receptor DopR2, two octopamine receptors (TyrR and oa2) and the Nmda-receptor associated protein Nmda1 all showed reduced body fat content following RNAi induction. In addition, altered fat deposition was observed in response to RNAi knockdown of known mediators of glucose/lipid mobilization including fructose-1,6-bisphosphatase (fbp), the two members of the glycerol phosphate shuttle (CG31169 and gpo-1), mitochondrial acyl-carrier protein (mtacp1), ADP/ATP translocase 2 (Ant2), pyruvate carboxykinae (CG1516), and fatty-acid synthetase (fasn). Also identified were the Drosophila orthologues of glucagon (akh), the insulin receptor (dInR), as well as the downstream kinases PI3-kinase (dPI3K), ribosomal-S6-kinase (dRSK), the CREB-coactivator dTORC, and the critical TOR-signaling constituent dTSC-1,

Drosophila homologues of the critical early adipogenic regulators NCOR1/2, Jag1/2, and TAK1 (Ross et al., 2004; Suzawa et al., 2003; Yu et al., 2005), or the metabolic regulators CRTC1/2 and pyruvate carboxylase (PC) (Altarejos et al., 2008; Koo et al., 2005; Zhang et al., 1995). We also hit the Drosophila lipoprotein rfabg (retinol fatty-acid binding glycoprotein) previously shown to transport key developmental morphogens such as hedgehog (Panakova, 2005). Indeed, “regulation of smoothened [hedgehog] signaling” was the most highly enriched signal transduction pathway in our gene-ontology analysis (FIG. 1G). Thus, our genome-wide approach identified multiple known molecular players previously associated with adipocyte development and function. Most importantly, the screen revealed a large number of candidate genes not previously associated with obesity.

Example 1.2 Tissue Specific Mapping of Candidate Obesity Genes

Considering the complexity of metabolism and the recognized diversity of tissue-specific processes that govern lipid-storage (Leopold and Perrimon, 2007; Speakman et al., 2008), we set out to functionally categorize the candidate lipid regulators according to tissue-specificity. RNAi-lines of the 462 primary screen candidate genes were crossed to four independent GAL4 drivers with pan-neuronal (nsyb-GAL4), muscle (C57-GAL4), oenocyte (oe-GAL4), and fat-body (ppl-GAL4) specificity, and their respective triglyceride levels determined (FIG. 3A). Interestingly, RNAi lines most strongly regulating fat-content after pan-neuronal (nsyb-GAL4) knockdown elicited little or no change in fly triglyceride levels when induced in the muscle, oenocyte or fat body (FIG. 3B). Muscle-specific gene silencing (C57-GAL4), by contrast, enriched for genes that also elicited significant changes in triglycerides when targeted in oenocytes and the fat-body (FIG. 3C). RNAi-lines responding most substantially to oenocyte and fat-body specific knockdown displayed a coordinate and reciprocal pattern of adiposity regulation (FIGS. 3D and 3E); these findings are in keeping with the tight regulatory interplay reported for these correlates of the mammalian adipose and liver (Gutierrez et al., 2007). GO analysis of the combined fat-enhancing and fat-diminishing gene sets for each of the four tissues tested are summarized in FIG. 3B-E. In support of the inducible design of the current screen, cell fate, cell differentiation and organ development pathways showed strong enrichment in the analysis (FIG. 3B-E, right panels: The neuronal hits (nsyb-GAL4) are: CG5436, CG2091, CG17461, CG11339, CG11202, CG5245, CG14911, CG30075, CG16836, CG5147, CG17184, CG10728, CG17742, CG4851, CG5381, CG18563, CG18268, CG10542, CG12015, CG4152, CG32669, CG32149, CG11756, CG12691, CG12595, CG32210, CG1279, CG17255, CG2260, CG14024, CG2146, CG7776, CG31132, CG3497, CG9936, CG10152, CG14842, CG6043, CG8515, CG9946, CG17819, CG11125, CG2145, CG12030, CG1759, CG1921, CG14303, CG6603, CG3906, CG30271, CG18740, CG12505, CG13202, CG8451, CG15507, CG6817, CG2818, CG12105, CG13423, CG32667, CG18586, CG17736, CG11376, CG11430, CG2898, CG4957, CG3054, CG12345, CG18414, CG14673, CG2254, CG32442, CG6122, CG13360, CG8298, CG6147, CG13319, CG33558, CG5625, CG13679, CG12806, CG3806, CG6064, CG15095, CG10691, CG3971, CG11505, CG3017, CG3108, CG3992, CG17754, CG14164, CG13332, CG3839, CG8443, CG7065, CG10632, CG1516, CG4247, CG4247, CG3004, CG31845, CG31744, CG9028, CG16826, CG13137, CG7082, CG6299, CG32091, CG30184, CG30491, CG11768, CG14968, CG17921, CG4415, CG5072, CG7199, CG4373, CG30411, CG14166, CG1555, CG2198, CG6947, CG6824, CG8079, CG1888, CG9295, CG14903, CG10617, CG10230, CG17781, CG17781, CG6721, CG7103, CG32170, CG3526, CG7737, CG11601, CG32336, CG1975, CG14909, CG11797, CG9922, CG11555, CG30470, CG17841, CG9153, CG31172, CG17335, CG7287, CG3396, CG13116, CG13984, CG33466, CG30065, CG14265, CG32234, CG2076, CG4038, CG14704, CG9053, CG30486, CG31219, CG1171, CG10840, CG6577, CG7099, CG1433, CG13673; The muscle (C57-GAL4) hits are: CG11339, CG18740, CG11376, CG7206, CG4583, CG12015, CG32667, CG14011, CG14024, CG11601, CG9634, CG12505, CG9695, CG14911, CG30486, CG12595, CG17754, CG9936, CG6009, CG1705, CG30080, CG32210, CG3817, CG8202, CG18268, CG31421, CG31692, CG31605, CG9748, CG14434, CG31161, CG12806, CG6947, CG3054, CG12770, CG6127, CG11505, CG1963, CG11555, CG5147, CG13319, CG4634, CG17819, CG32091, CG9160, CG18279, CG18279, CG32467, CG8337, CG8239, CG12259, CG3911, CG8654, CG1279, CG32140, CG7776, CG6892, CG13984, CG2091, CG17026, CG33204, CG11121, CG3497, CG6122, CG15321, CG6949, CG14375, CG10687, CG17283, CG14903, CG10101, CG14677, CG7830, CG9056, CG32459, CG2254, CG1422, CG17867, CG17781, CG17781, CG4373, CG3879, CG11756, CG10916, CG10809, CG15390, CG14265, CG9322, CG1650, CG6299, CG5550, CG2260, CG11570, CG10369, CG16836, CG30075, CG2076, CG3213, CG9220, CG31132, CG13868, CG1180, CG14166, CG14095, CG13127, CG31061, CG14362, CG32401, CG7796, CG1728, CG9506, CG3260, CG15625, CG7779, CG8107, CG30411, CG7103, CG7485, CG9676, CG3809, CG2702, CG15646, CG13972, CG14968, CG12664, CG12997, CG12997, CG4957, CG14869, CG3274, CG5719, CG5591, CG11133, CG7847, CG11768, CG8721, CG9258, CG5674, CG17184, CG13673, CG17461, CG11404, CG1622, CG9554, CG13707, CG13344, CG4264, CG10772, CG13360; The oenocyte hits (oe-GAL4) are: CG12505, CG33204, CG4207, CG15507, CG1683, CG32353, CG17461, CG11202, CG15432, CG9198, CG9295, CG1490, CG7830, CG31161, CG9028, CG3497, CG14265, CG4944, CG11229, CG11376, CG3825, CG31484, CG32210, CG1705, CG11339, CG11133, CG3806, CG3971, CG13807, CG18414, CG10166, CG12015, CG6127, CG14234, CG12595, CG17596, CG7292, CG2898, CG32091, CG17754, CG5625, CG10632, CG9634, CG2145, CG10084, CG10728, CG3526, CG6967, CG5270, CG15115, CG3425, CG9485, CG13707, CG8009, CG9160, CG33558, CG6892, CG14024, CG6689, CG3906, CG8079, CG1874, CG1516, CG5674, CG12184, CG2852, CG9438, CG6054, CG17921, CG15599, CG8202, CG33466, CG14362, CG2540, CG7352, CG9695, CG1572, CG13319, CG3313, CG13188, CG13137, CG31744, CG30360, CG3893, CG5436, CG3696, CG4851, CG7287, CG10916, CG8527, CG14909, CG3004, CG7213, CG1422; CG9760, CG30486, CG32234, CG13088, CG3440, CG4373, CG7485, CG14936, CG11425, CG10152, CG12345, CG15582, CG15646, CG8693, CG11404, CG15625, CG11125, CG2374, CG14677, CG2702, CG32401, CG9676, CG1622, CG13299, CG8107, CG31421, CG3879, CG5719, CG7737, CG4271, CG13168, CG31692, CG10101, CG17867, CG16758, CG32170, CG7796, CG5641, CG10369, CG17283, CG30184, CG9220, CG3017, CG30462, CG30462, CG31605, CG14968, CG12664, CG6299, CG2984, CG14341, CG8250, CG9399, CG3809, CG9506, CG8444, CG2818, CG31812, CG7103, CG3523, CG30065; and the fat-body hits (ppl-GAL4) are: CG17461, CG15432, CG11339, CG32091, CG9565, CG3839, CG13972, CG30183, CG6721, CG14011, CG13243, CG12323, CG5245, CG11267, CG8515, CG32210, CG8654, CG2260, CG3274, CG9554, CG31845, CG8337, CG8190, CG6788, CG11376, CG3497, CG11229, CG17754, CG31697, CG32467, CG18402, CG2146, CG3523, CG30470, CG30075, CG1975, CG4264, CG32442, CG9322, CG9160, CG10632, CG16836, CG6949, CG6147, CG8079, CG3817, CG5595, CG12806, CG3980, CG16903, CG9487, CG7099, CG13744, CG11133, CG3992, CG9952, CG12875, CG7091, CG3440, CG6156, CG4038, CG32791, CG31484, CG1433, CG10687, CG5625, CG9258, CG6892, CG7776, CG31812, CG30080, CG7199, CG17331, CG6277, CG14016, CG14016, CG1874, CG5071, CG9144, CG12015, CG13332, CG32667, CG1888, CG33466, CG12602, CG31693, CG6580, CG12595, CG9056, CG7779, CG7796, CG5495, CG8298, CG15115, CG3260, CG17985, CG8534, CG4202, CG3108, CG3906, CG6054, CG3971, CG7830, CG5688, CG13868, CG7292, CG18767, CG14434, CG12184, CG11621, CG6356, CG9086, CG15646, CG10542, CG6689, CG3425, CG7206, CG11575, CG5719, CG32669, CG15579, CG1722, CG7287, CG4394, CG9220, CG14164, CG14164, CG14164, CG14704, CG3809, CG15169, CG11570, CG18319, CG31690, CG1531, CG7847, CG31692, CG4583, CG13088, CG8566, CG8107, CG32971, CG31421, CG3054, CG15390, CG14869, CG8444, CG30476, CG3879, CG2145, CG3017, CG10809, CG32459, CG14166, CG14936, CG4957, CG14095, CG8665, CG13984, CG13188, CG17841, CG32170, CG12105, CG14968, CG5381, CG18268, CG13299, CG17781, CG17781, CG4271, CG5641, CG8693, CG32140, CG32353, CG30065, CG14909, CG3893, CG6577, CG10152, CG17867, CG13116, CG3843, CG9153, CG30184, CG2984, CG1180, CG14341, CG11404, CG1622, CG32234, CG9506, CG4373, CG2374, CG12997, CG12997, CG13423, CG1963, CG5674, CG14362, CG13344, CG8250. Thus, we provide functional annotation of −500 candidate obesity genes in four key metabolic tissues in Drosophila.

Example 1.3 Neuronal Hits

In mammals, the leptin/AgRP/POMC axis exemplifies the profound neuronal dependency of feeding behaviour, metabolic rate, insulin resistance and thus, of obesity risk. Flies do not possess known homologues to this axis but their feeding behavior is also neuronally anchored. Approximately one third of the primary screen hit list elicited triglyceride changes >25% when crossed with the neuronal nsyb-GAL4 driver. A select number exhibited tight neuronal restriction in their response (FIG. 5A). Included was the Drosophila homologue for SLC5A8 (CG8451; FIG. 5A) a neuronal fatty-acid and lactate transporter. In rodents, fatty acids are sensed by neuronal processing of lactate generated by adjacent glial cells. Similarly, lines targeting homologues of glucagon (akh, neuronally secreted in Drosophila), and the neuronal Zn-transporter SLC39A10 both displayed tight neuronal responses. Also, TSC1 (dTSC1), a critical regulator of the amino acid responsive TOR-signaling pathway, showed marked neuronal and fat-body specific responsiveness (FIG. 5D). It is likely that aside from peripheral regulation of nutrient storage, TOR signaling in the CNS might relay amino acid status to feeding behaviour. Additional neuronal responsive targets likely to play a direct role in nutrient sensing included the odorant/gustatory receptors Obp56a and TyR. Thus, similar to mammals, fat storage in Drosophila appears regulated by a complex network of neuronal genes.

Example 1.4 Muscle Hits

Several genes showed tight muscle-specificity (FIG. 5B), including homologues of the proline biosynthetic PYCR1 (P5cr), the glycogen debranching enzyme AGL (CG9485), and the fbp (fructose-1,6-bisphosphatase), a key regulator of glycolysis. Mevalonate decarboxylase (CG8239), which supports cholesterol biosynthesis and is currently being tested therapeutically to reduce cholesterol levels, showed similar muscle-specificity as did the sterol regulating enzyme ARV1 (CG32442). Mutants of ARV1 have previously been shown to exhibit altered lipid metabolism. Interestingly, genes involved in TLR-signaling (IM10), the ribosome and protein translation (CG3213), proteolysis (Furl), transcriptional regulation (CG5591), and microRNA mediated silencing (5 mg5) (FIG. 5B) were also found to regulate triglyceride level specifically in muscle cells.

Example 1.5 Fat and Oenocyte Candidate Genes

The largest number of primary screen hits showed oenocyte-(oe-GAL4) and fat-body-(ppl-GAL4) responses (FIG. 5C,D). Interesting targets included homologues of inflammation-related genes: ARID2 (regulates interferon responsive genes (Yan et al., 2005), dTraf (fly Traf-like protein), the pattern recognition receptor PGLYRP2, the interleukin enhancer binding factor ILF2, the extracellular matrix protein tenascin (TNC), the ubiquitin-conjugating enzyme UBE2N (critical for TNF- and Toll-like-receptor signaling), or the de-ubiquitinating enzyme USP7. Additional components of the ubiquitin-ligase machinery were also revealed, namely UBR2, HERC4, and FBWX5 (also controls TSC1 and thus TOR-signaling). Together these data support roles for immune regulatory networks and ubiquitination in fat storage regulation in Drosophila.

Oenocyte- and fat body-specific knockdown analyses also identified genes involved in glycerol and lipid metabolism (FIG. 5C,D). For instance, genes related to insulin signaling including the homologues of PP1 (inhibitory subunit 15b), S6KII, EIF2B, PI3K, and the insulin receptor itself (IR). Also, direct mediators of lipid and glucose metabolism were identified, such as homologues of the ADP/ATP symporter ANT, NDUFAB1, GDPD, and GPD2. The latter, part of the glycerol-phosphate shuttle, regulates glycolytic rate and ROS production. Of interest, mice lacking GPD2 exhibit a 40% reduction in white adipose mass (Brown et al., 2002) and share a number of phenotypic features with deficiencies of glycerol kinase (GK), another enzyme found using the oenocyte-specific driver. In addition, we found T3dh (an iron-dependent regulator of fatty acid and ketone body metabolism), Cyp6a2 (cytochrome P450 proteins catalyze numerous steps of cholesterol, steroids and lipids synthesis), and particularly robust in both the oenocyte- and fat-body analyses, the Drosophila homologue of the fatty acid elongase ELOVL6. Elov16^(−/−) mice develop marked obesity and hepatosteatosis and show protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia (Matsuzaka et al., 2007). Using fat-body specific knockdown we also hit the Drosophila homologue of ELOVL7. Perhaps most importantly, we found multiple previously uncharacterized genes that regulate fat content in an oenocyte- and/or fat body-dependent manner (FIG. 5C,D). Thus, our screen has revealed a large number of general and tissue specific candidate fly genes and multiple pathways that control triglyceride storage levels.

Example 2 Mouse In Vivo Pathway Modulation

The biological process “regulation of smoothened [hedgehog] signaling” was one of the most prominent signal transduction pathway of all pathways in the primary screen. An additional 8 potential hedgehog signalling members recently identified in a Drosophila S2 cell screen for modulators of hedgehog signalling (Nybakken et al., 2005) were also hit in our primary obesity screen. Together these represent a >20-fold enrichment for the hedgehog signaling pathway. Importantly, hedgehog signaling scored third in fat-body-responsive pathways while not scoring at all in muscle or neuronal datasets (FIG. 5E; FIG. 6A). Hedgehog modulation has been suggested previously as a target for obesity therapies (Suh et al. Cell Metabolism, 2006; WO2000/51628). We therefore homed into the hedgehog pathway to provide proof of principle for the fly screen and to translate our Drosophila results directly into the mammalian context.

To assess the in vivo relevance of the drosophila screen results, hedgehog signaling in mammalian adipogenesis was further investigated. Fat-specific Sufu knockout animals (aP2-SufuKO) were generated (FIG. 8C). Sufu is a potent endogenous inhibitor of hedgehog signaling in mammals. Sufu^(flox/flox) mice were crossed to the adipose-tissue deleting aP2-Cre transgenic line (FIG. 8C) and the resulting aP2-SufuKO animals were born healthy and at Mendelian ratios. PCR amplification revealed target deletion in both white (WAT) and brown (BAT) adipose tissue (FIG. 7A,D). aP2-SufuKO mice displayed an immediate and obvious lean phenotype. MRI analysis revealed a significant and global reduction in white adipose tissue mass, including subcutaneous, perigonadal, and mesenteric depots (FIG. 7B). Intriguingly though, in contrast to the gross loss of WAT, cross-sectional examination of the interscapular region revealed fully developed BAT depots of both normal size and lipid content (FIG. 7B,C). Direct measurement of WAT and BAT depot weights corroborated the divergent WAT/BAT phenotype, with an ˜85% reduction in perigonadal fat pad mass in aP2-SufuKO mice concomitant with unaltered BAT mass (FIG. 7E, FIG. 8D). Tissue weight and histological analyses confirmed lack of any remarkable phenotype in multiple other tissues including pancreas and liver (no indication of steatosis), and muscle mass was unaffected (FIG. 8D). Cutaneous adipose was also markedly diminished (FIG. 8E). Whereas the morphology of Sufu-deficient BAT depots was largely indistinguishable from that of control animals (FIG. 7E,F), examination of multiple WAT pads revealed marked and significant reductions in both adipocyte size (FIG. 7E,G; FIG. 8F) and total numbers (FIG. 8G) in mutant animals. Of note, qPCR showed elevated Gli1, Gli2, and Ptch2 expression in both WAT (FIG. 7H) and BAT (FIG. 7I), verifying the intended pathway activation in both tissues. Thus, deletion of Sufu in fat tissue results in a markedly decreased white fat cell number and, remarkably, in normal brown adipose tissue. These results demonstrate that hedgehog activation results in a virtually complete block of WAT development but leaves the differentiation process of brown adipocytes wholly intact.

Example 3 Testing of Active Compounds

General preferred layout: The mice were divided into cages of 2-4 mice per cage and allowed to acclimatise to the new housing conditions for at least 2 weeks. The mice were weighed every week to monitor their weight and ensure that the mice are either gaining weight or stabilized prior to initiation of the experiment. Mice were randomly assigned to weight-matched groups for compound administration. Compound dosage and routes of administration were determined based on published literature and pharmacokinetic studies.

To test the positive candidates in mice the following protocol was used: JAX® DIO B6 mice, 18 weeks of age, were divided into groups of 2-4 mice of equivalent body weight upon receipt from Jax labs. The Jax labs protocol for feeding and care of diet-induced obese (DIO) C57BL/6J mice is as follows: Male mice are selected at random at four weeks of age and fed a 6% fat (wt/wt) chow diet (Lab Diet® 5k52). At six weeks of age, mice are placed in wean cages in groups of 10 and are fed high fat diet to induce obesity (Research Diets, Inc. D124921, 60 kcal % fat). Mice have ad libitum access to food and water. Upon receipt of the animals from Jax labs, animals were kept under similar housing and feeding conditions to those at Jax labs ie. mice continued to receive a high fat diet (Test Diet® 58Y1 60% energy from Fat).

In special methods following protocol was used: Modulator compounds of the new identified genes responsible for triglyceride or fat regulation underwent two rounds of testing. The first round screened all candidate compounds in Drosophila, and positive candidates were subsequently tested in mice induced to be obese through administration of a high fat diet. Two day old W1118 male Drosophila melanogaster were sorted 20 flies per vial and placed for one week on normal fly food in the presence or absence of each test compound. Test compounds were added to the surface of the fly food in liquid form and allowed to absorb into the top-most layer at 3 doses 0.001 umol/kg/day, 1 umol/kg/day, and 1000 umol/kg/day.

After one week of treatment flies were shock-heated to dryness, and dry weight used as an indicator of adiposity. All flies with dry weights <75% of the mean value of control vials were considered positive candidates with obesity lowering activity. Those positive candidates which induced obvious behavioural impairment were removed from the group of positive candidates. Behavioural tests included tapping of the vial (flies should jump into flight) and exposure to light (flies should move towards a light source). All remaining positive candidates were taken forward for analysis in mice.

To test the positive candidates in mice the following protocol was used: JAX® DIO B6 mice, 12 weeks of age, were divided into groups of 8-10 mice of equivalent body weight upon receipt from Jax labs. The Jax labs protocol for feeding and care of diet-induced obese (DIO) C57BL/6J mice is as follows: Male mice are selected at random at four weeks of age and fed a 6% fat (wt/wt) chow diet (Lab Diet® 5k52). At six weeks of age, mice are placed in wean cages in groups of 10 and are fed high fat diet to induce obesity (Research Diets, Inc. D124921, 60 kcal % fat). Mice have ad libitum access to food and water. Upon receipt of the animals from Jax labs, animals were kept under identical housing and feeding conditions to those at Jax labs ie. mice continued to receive the high fat diet listed above. For all substances known to be orally available in mammals, mice were treated in drinking water at 5× and 250× the recommended human therapeutic dose. For other compounds dosing was based on published pharmacokinetics in mice or, where unavailable, based on the lowest functional dose in flies (ie. the 1× and 50× the low-est functional dose in flies). Compounds known to be orally unavailable in mammals were administered once daily by manual injection i.p. in a cellulose injection vehicle at doses determined as above. Body weight as well as food and water intake were monitored over the two week treatment period, and where mean body weight reductions relative to control animals were significant by t-test (p<0.05) and exceeded 2 g (˜5% of body weight) body fat composition was assessed by weighing total body weight, as well as peri-gonadal and subcutaneous fat pad weight at sacrifice. Compounds where changes in body weight correlate directly with changes in body fat composition were considered positive therapeutic candidates for treating mammalian obesity.

Example 3.1 Administration of Vandetanib

Vandetanib also known as ZD6474 is a tyrosine kinase inhibitor that functions as an antagonist of the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR).

Vandetanib powder was obtained from Selleck Chemicals (S1046). Male C57B16/J DIO mice of 30 weeks of age were weight matched and housed in groups of 2 mice per cage and kept on 12-h light-dark cycle. Food and water were given ad libitum. 8 compound administered mice (experimental) and 7 vehicle administered mice (control) were included in the experiment.

Mice were administered a daily dose of Vandetanib by oral gavage. Vandetanib was delivered in a vehicle consisting of 1% tween in PBS. Control mice were administered vehicle alone, daily, by oral gavage.

The dose of Vandetanib chosen for this study was 40 mg/kg/d. This has been determined to be an effective dose for the inhibition of the target VEGFR in various mouse cancer models. In Choi et al 2008, Vandetanib was administered at a dose of 50 mg/kg/d by oral gavage in a vehicle of 1% tween 80 with PBS for 4 weeks in an orthopic nude mouse model of human Adenoid Cycstic Carcinoma. During the treatment period vandetanib was well tolerated by the mice and no adverse side effects or loss in body weight was observed (Choi et al 2008). This dose was effective to significantly reduce tumour volume compared to vehicle administered controls (Choi et al 2008). Treatment at a dose of 50 mg/kg for 21 days in a renal cell carcinoma mouse model was well tolerated with no drug related changes in weight or behaviour observed (Drevs et al., 2004). This dose was also effective to reduce primary tumour volume (Drevs et al., 2004). Dosing in mice with Vandetanib in preclinical studies range from 12.5 to 150 mg/kg/day (Wedge et al., 2002; Ciardiello et al., 2003; Taguchi et al., 2004; Damiano et al., 2005). Generally a dose above 25 mg/kg/day leads to an inhibition of tumour growth or induction of tumour regression whereas doses at or below this level tend to lead to a slowing of tumour growth (Wedge et al., 2002; Gustafson et al., 2006). Vandetanib has been administered to mice up to a dose of 100 mg/kg in mice for 35 days with no obvious effect on clinical condition (Wedge et al., 2002). The DIO mice were weighed on the same day prior to the first compound administration (day 1). The mice were weighed on a daily basis during the experiment and monitored for overt signs of toxicity or stress. Vandetanib was well tolerated during the course of the study and no adverse side effects were observed. We observed an increased loss of weight in the compound administered mice compared to the vehicle administered controls (FIG. 1). By day 13 we observed a statistically significant weight loss in the vandetanib administered mice compared to controls which was maintained for the duration of the experiment (p<0.05; unpaired student t test).

On day 7 an Insulin tolerance test was performed (FIG. 10) Although the insulin response was similar in both experimental and control groups, we did observe a significant reduction in fasting glucose levels in the experimental mice compared to the controls (p<0.05).

On day 35 an oral glucose tolerance test was performed (FIG. 11). We observed a reduction in the level of glucose levels at the 15, 45 and 60 minute time point after glucose administration indicating that the vandetanib administered mice show an improved insulin response compared to controls (p<0.05).

On day 38 of compound administration the mice were sacrificed. The perigonadal fat pads were isolated and weighed. These values were expressed as a proportion of the body length of the mouse (FIG. 12). We observed a reduction of fat pad weight in the vandetanib administered group indicating the loss of weight in these mice is due to loss of fat pad mass (p<0.05; unpaired student t test).

Taken together these data indicate that Vandetanib leads to an almost 10% reduction of body weight that stabilized over the course of the experiment. The reduction in blood glucose levels and improvement of glucose handling are consistent with the observed reduction in adiposity.

Example 3.2 Administration of Dasatinib

Dasatinib is a multiple BCR/abl Src family tyrosine kinase inhibitor. It is approved for use in the treatment of chronic myelogenous leukaemia.

Dasatinib was obtained as a powder from Selleck chemicals. C57B16/J DIO mice of 19 weeks of age and weighing more than 33 g were weight matched and housed in groups of 4 mice per cage and kept on 12-h light-dark cycle. Food and water were given ad libitum. 5 dasatinib administered mice (experimental) and 4 vehicle administered mice (controls) were used in the experiment. Mice were administered a dose of 5 mg/kg/day daily of Dasatinib intraperitoneally in a vehicle of 1:1 propylene glycol/water. Control animals were administered the vehicle alone.

1.25 mg/kg/dose BID or 2.5 mg/kg/dose QD are considered to be the minimum efficacious dose based on studies in severe combined immunodeficient mice bearing s.c. K562 xenografts (Lee et al., 2004). The preclinical efficacious dose of 2.5 mg/kg/day is approximately equivalent to a clinical does of 25 mg/day (Luo et al., 2006). A dosing regimen in mice of 5 mg/kg, PO) closely mimics the pharmacokinetics of the approved human once-daily dose of 100 mg. Based on this we decided to administer a dose of 5 mg/kg/day in obese mouse models.

The DIO mice were weighed on the same day prior to the first compound administration (day 1). The mice were weighed on a daily basis during the experiment and monitored for overt signs of toxicity or stress. Dasatinib was well tolerated during the course of the study and no adverse side effects were observed. We observed a significant weight loss in the dasatinib administered mice compared to the vehicle administered controls (FIG. 13). On day 5 we observed a significant weight reduction in the dasatinib group and by day 28 these mice had lost an average of 20% of their starting weight. This represented a statistically significant loss compared to vehicle administered mice (p<0.001; unpaired student t test).

On day 15 an oral Glucose tolerance test was performed. Although both groups exhibit a similar fasting glucose level (time 0) there is an improved insulin response 15, 30 and 45 minutes after glucose administration in the experimental group (FIG. 14). This indicates that dasatinib leads to an improvement in insulin response and glucose clearance in mice fed a high fat diet. On day 29 an oral glucose tolerance test was performed. We compared the glucose measurements to that of the fasting glucose levels at time 0 (taken as 100%) in each group to determine the relative changes in glucose clearance (FIG. 15). We observed an improved glucose clearance in the dasatinib administered mice (45 mins p<0.05; 60 mins p<0.01). Taken together the improvements in insulin sensitivity and glucose handling are consistent with the observed reduction in weight.

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1.-18. (canceled)
 19. A method for reducing weight and/or body fat in a subject comprising: obtaining a therapeutic compound; and administering a dose of the therapeutic compound to a subject; wherein weight and/or body fat is reduced in the subject.
 20. The method of claim 19, wherein the compound is Vandetanib.
 21. The method of claim 19, wherein the compound is Dasatinib, Tanespimycin, S-17092, or Sorafenib.
 22. The method of claim 19, wherein the compound is Lintopride, Fenoprofen, Sulfaphenazole, Fluticasone, Rolipram, Febuxostat, or Verapamil.
 23. The method of claim 19, wherein the compound is a modulator of gene CG9438 or an ortholog thereof.
 24. The method of claim 23, wherein the compound erlotinib, gefitinib, or lapatinib.
 25. The method of claim 19, wherein the compound is modulator of gene CG8222 or an ortholog thereof.
 26. The method of claim 25, wherein the compound is axitinib, pazopanib, or semaxanib.
 27. The method of claim 19, wherein the compound is a modulator of gene CG6919 or an ortholog thereof.
 28. The method of claim 27, wherein the compound is cisapride, mosapride, piboserod, prucalopride, renzapride, tegaserod, tropisetron, or zacopride.
 29. The method of claim 19, wherein the compound is administered in combination with any one or more therapeutic compound of table
 1. 30. The method of claim 19, wherein the subject is obese.
 31. The method of claim 30, wherein the subject has a body-mass-index (BMI) of at least
 35. 32. The method of claim 31, wherein the subject has a body-mass-index (BMI) of at least
 40. 33. The method of claim 19, wherein the compound is administered topically, enterally, or parenterally.
 34. The method of claim 33, wherein the compound is administered orally, rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intradermally, intraperitoneally, transdermally, transmucosally, or via inhalationa.
 35. The method of claim 19, wherein the subject is a mammal.
 36. The method of claim 35, wherein the subject is a human.
 37. The method of claim 19, wherein the compound is provided in a medicament.
 38. The method of claim 19, wherein the compound is comprised in a pharmaceutically acceptable carrier or buffer.
 39. The method of claim 19, wherein the dose is between 0.01 mg/kg and 1 g/kg.
 40. The method of claim 19, wherein the compound is administered as the only therapeutic compound active in a treatment of reducing weight and/or body fat or of obesity in the subject. 